Methods for synthesis of prodrugs from 1-acyl-alkyl derivatives and compositions thereof

ABSTRACT

The present invention provides a method for synthesizing 1-(acyloxy)-alkyl derivatives from 1-acyl-alkyl derivatives, which typically proceeds stereospecifically, in high yield, does not require the use of activated intermediates and/or toxic compounds and is readily amenable to scale-up. The current invention also provides 1-acyl-alkyl derivatives of known drug compounds and methods for synthesizing these 1-acyl-alkyl derivatives.

[0001] This application claims the benefit under 35 U.S.C. §119(e) fromU.S. Provisional Application Serial No. 60/358,603, filed Feb. 19, 2002;and U.S. Provisional Application Serial No. 60/371,535, filed Apr. 9,2002, which are herein incorporated by reference.

1. FIELD OF THE INVENTION

[0002] The present invention relates generally to methods for synthesisof 1-(acyloxy)-alkyl derivatives. More particularly, the presentinvention relates to the synthesis of prodrugs (i.e., 1-(acyloxy)-alkylderivatives of pharmacologically effective drugs) from 1-acyl-alkylderivatives of pharmacologically effective drugs and to new compoundswhich are 1-acyl-alkyl derivatives of pharmacologically effective drugs.

2. BACKGROUND OF THE INVENTION

[0003] One solution to drug delivery and/or bioavailability issues inpharmaceutical development is converting known drugs to prodrugs.Typically, in a prodrug, a polar functional group (e.g., a carboxylicacid, an amino group, a hydroxyl group, etc.) is masked by a promoiety,which is labile under physiological conditions. Accordingly, prodrugsare usually transported through hydrophobic biological barriers such asmembranes and typically possess superior physicochemical properties incomparison to the parent drug.

[0004] Pharmacologically effective prodrugs are non-toxic and arepreferably selectively cleaved at the locus of drug action. Ideally,cleavage of the promoiety occurs rapidly and quantitatively with theformation of non-toxic by-products (i.e., the hydrolyzed promoiety).

[0005] The acyloxyalkoxycarbonyl functionality is an example of apromoiety that may be used to modulate the physiochemical properties ofpharmaceuticals (Alexander, U.S. Pat. No. 4,916,230; Alexander, U.S.Pat. No. 5,733,907; Alexander et al., U.S. Pat. No. 4,426,391).Typically, 1-(acyloxy)-alkyl derivatives of pharmaceuticals possesssuperior bioavailability, are usually less irritating to topical andgastric mucosal membranes and more permeable through such membranes,when compared to the parent drugs.

[0006] However, although 1-(acyloxy)-alkyl ester derivatives of alcoholsand 1-(acyloxy)-alkyl carbamate derivatives of amines have beenfrequently used to mask these polar functional groups inpharmaceuticals, existing synthetic methods for preparing thesedesirable prodrugs are inadequate. Existing methods for synthesis ofacyloxyalkyl esters and carbamates are typically multi-step routes thatutilize unstable intermediates and/or toxic compounds or salts and aredifficult to perform on a process scale (Alexander, U.S. Pat. No.4,760,057; Lund, U.S. Pat. No. 5,401,868; Alexander, U.S. Pat. No.4,916,230; Saari et al., European Patent 0416689B1).

[0007] Although, 1-acyl-alkyl derivatives of drugs are known in the art(Sakamoto et al, Chem. Pharm. Bull. 1985, 33, 4870-4877; Hayashibe etal, International Publication No. WO 00/59913; Hartmann et al,International Publication No. WO 96/40156; Bal-Tembe et al, Bioorg. Med.Chem. 1997, 5, 1381-1387; Dow et al, European Patent Application No.EP1088819; Hong et al, Eur. J. Cancer Clin. Oncol. 1983, 19, 1105-1112;Ogata, K. Jpn. Kokai Tokkyo Koho JP 2001002690; Ashton et al,International Publication No. WO 95/20567; and Charpiot et al, Bioorg.Med. Chem. 2001, 9, 1793-1805) these compounds have not been convertedto 1-(acyloxy)-alkyl prodrug derivatives. Accordingly, there is a needfor a new synthesis of 1-(acyloxy)-alkyl derivatives that proceedsrapidly and efficiently, without the use of activated intermediatesand/or toxic compounds, which is amenable to scale-up and proceedsthrough readily accessible synthetic precursors. Further, there is alsoa need for 1-acyl-alkyl derivatives, which may serve as syntheticprecursors to 1-(acyloxy)-alkyl derivatives.

3. SUMMARY OF THE INVENTION

[0008] The present invention satisfies these and other needs byproviding a method for synthesizing 1-(acyloxy)-alkyl derivatives from1-acyl-alkyl derivatives, which typically proceeds stereospecifically,in high yield, does not require the use of activated intermediatesand/or toxic compounds and which may provide process scale amounts of1-(acyloxy)-alkyl compounds. The instant invention also provides1-acyl-alkyl derivatives of known drug compounds and methods forsynthesizing these 1-acyl-alkyl derivatives

[0009] In one aspect, the present invention provides 1-acyl-alkylderivatives comprising compounds of structural Formula (I):

[0010] or a pharmaceutically acceptable salt, hydrate or solvatethereof, wherein:

[0011] n is 0 or 1;

[0012] q is 0 or 1;

[0013] provided that n and q are 0 unless Y is —NRR′ or —OR;

[0014] Y is —NRR′, —OR, —C(O)R, —P(O)(OR′)R or —P(O)(OR′)(OR), wherein:

[0015] —NRR′ is derived from a drug containing a primary or secondaryamino group, with the proviso that the drug is not norfloxacin,pamidronate or a 2-aminomethyl-3-methylthiazolo[3,2a]benzimidazolederivative;

[0016] —OR is derived from a drug containing a hydroxyl group, with theproviso that the drug is not 1-hydroxymethyl 5-fluorouracil or a1-aryl-6,7-dialkoxyisoquinolone phosphodiesterase inhibitor;

[0017] —OC(O)R is derived from a drug containing a carboxylic acid orcarboxylate group, with the proviso that the drug is not a6-azauracil-5-carboxylic acid derivative;

[0018] —OP(O)(OR′)R is derived from a drug containing a phosphonic acidor phosphonate group;

[0019] —OP(O)(OR′)(OR) is derived from a drug containing a phosphoricacid or phosphate group, with the proviso that the drug is notcytarabine-5′-phosphate or α-tocopherol phosphate;

[0020] R¹ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl or a C₂₃ bileacid moiety or optionally, R¹ and either R² or R³, together with theatoms to which R¹ and R² or R³ are attached, form a cycloalkyl,substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkylring, which is optionally fused to an aryl, substituted aryl,heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring;

[0021] R² and R³ are independently hydrogen, alkyl, substituted alkyl,alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substitutedcycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl,heteroaryl, substituted heteroaryl, heteroarylalkyl or substitutedheteroarylalkyl or optionally, R² and R³ together with the atom to whichthey are attached form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring;

[0022] R²¹ is independently hydrogen, alkyl or substituted alkyl; and

[0023] R²² is independently hydrogen, alkyl, substituted alkyl, alkoxy,substituted alkoxy, acyl, substituted acyl, acylamino, substitutedacylamino, alkylamino, substituted alkylamino, alklysulfinyl,substituted alkylsulfinyl, alkylsulfonyl, substituted alkylsulfonyl,alkylthio, substituted alkylthio, alkoxycarbonyl, substituted alkylthio,aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryloxy,substituted aryloxy, carbamoyl, substituted carbamoyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,dialkylamino, substituted dialkylamino, halo, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl, heteroalkyloxy, substituted heteroalkyloxy,heteroaryloxy, substituted heteroaryloxy or optionally, R²² togetherwith the carbon atom to which it is attached, the adjacent nitrogen atomand R²¹ substituent form a cycloheteroalkyl or substitutedcycloheteroalkyl ring.

[0024] In another aspect, the present invention provides a method ofsynthesizing a 1-(acyloxy)-alkyl derivative of structural Formula (II),which comprises oxidation of a compound of structural Formula (I) bycontacting the compound of Formula (I) with an oxidant to form acompound of Formula (II):

[0025] where n, q, Y, R¹, R², R³, R²¹, R²² and q are as defined above.The oxidant may be an organism (e.g., yeast or bacteria) or a chemicalreagent (e.g., an enzyme or a peroxide).

4. DETAILED DESCRIPTION OF THE INVENTION 4.1 Definitions

[0026] “Compounds of the invention” refers to compounds encompassed bystructural Formulae (I), (IV) and (V) disclosed herein, and includes anyspecific compounds within these Formulae whose structure is disclosedherein. The compounds of the invention may be identified either by theirchemical structure and/or chemical name. When the chemical structure andchemical name conflict, the chemical structure is determinative of theidentity of the compound. The compounds of the invention may contain oneor more chiral centers and/or double bonds and therefore, may exist asstereoisomers, such as double-bond isomers (i.e., geometric isomers),enantiomers or diastereomers. Accordingly, the chemical structuresdepicted herein encompass all possible enantiomers and stereoisomers ofthe illustrated compounds including the stereoisomerically pure form(e.g., geometrically pure, enantiomerically pure or diastereomericallypure) and enantiomeric and stereoisomeric mixtures. Enantiomeric andstereoisomeric mixtures can be resolved into their component enantiomersor stereoisomers using separation techniques or chiral synthesistechniques well known to the skilled artisan. The compounds of theinvention may also exist in several tautomeric forms including the enolform, the keto form and mixtures thereof. Accordingly, the chemicalstructures depicted herein encompass all possible tautomeric forms ofthe illustrated compounds. The compounds of the invention also includeisotopically labeled compounds where one or more atoms have an atomicmass different from the atomic mass conventionally found in nature.Examples of isotopes that may be incorporated into the compounds of theinvention include, but are not limited to ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl. Further, it should be understood, whenpartial structures of the compounds of the invention are illustrated,that brackets of dashes indicate the point of attachment of the partialstructure to the rest of the molecule.

[0027] “Composition of the invention” refers to at least one compound ofthe invention and a pharmaceutically acceptable vehicle, with which thecompound is administered to a patient. When administered to a patient,the compounds of the invention are administered in isolated form, whichmeans separated from a synthetic organic reaction mixture.

[0028] “1-Acyl-Alkyl Derivatives” refers to N-1-acyl-alkoxycarbonylderivatives of a primary or secondary amine; O-1-acyl-alkoxycarbonylderivatives of an alcohol; 1-acyl-alkyl esters of a carboxylic acid;1-acyl-alkyl esters of a phosphonic acid; and 1-acyl-alkyl esters of aphosphoric acid.

[0029] “1-(Acyloxy)-Alkyl Derivatives” refers toN-1-(acyloxy)-alkoxycarbonyl derivatives of a primary or secondaryamine; O-1-(acyloxy)-alkoxycarbonyl derivatives of an alcohol;1-(acyloxy)-alkyl esters of a carboxylic acid; 1-(acyloxy)-alkyl estersof a phosphonic acid; and 1-(acyloxy)-alkyl esters of a phosphoric acid.

[0030] “Alkyl” refers to a saturated or unsaturated, branched,straight-chain or cyclic monovalent hydrocarbon radical derived by theremoval of one hydrogen atom from a single carbon atom of a parentalkane, alkene or alkyne. Typical alkyl groups include, but are notlimited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propylssuch as propan-1-yl, propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl,prop-1-en-2-yl, prop-2-en-1-yl (allyl), cycloprop-1-en-1-yl;cycloprop-2-en-1-yl, prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls suchas butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl,cyclobutan-1-yl, but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl,but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

[0031] The term “alkyl” is specifically intended to include radicalshaving any degree or level of saturation, i.e., groups havingexclusively single carbon-carbon bonds, groups having one or more doublecarbon-carbon bonds, groups having one or more triple carbon-carbonbonds and groups having mixtures of single, double and triplecarbon-carbon bonds. Where a specific level of saturation is intended,the expressions “alkanyl,” “alkenyl,” and “alkynyl” are used.Preferably, an alkyl group comprises from 1 to 20 carbon atoms, morepreferably, from 1 to 10 carbon atoms.

[0032] “Alkanyl” refers to a saturated branched, straight-chain orcyclic alkyl radical derived by the removal of one hydrogen atom from asingle carbon atom of a parent alkane. Typical alkanyl groups include,but are not limited to, methanyl; ethanyl; propanyls such aspropan-1-yl, propan-2-yl (isopropyl), cyclopropan-1-yl, etc.; butanylssuch as butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl(isobutyl), 2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; andthe like.

[0033] “Alkenyl” refers to an unsaturated branched, straight-chain orcyclic alkyl radical having at least one carbon-carbon double bondderived by the removal of one hydrogen atom from a single carbon atom ofa parent alkene. The group may be in either the cis or transconformation about the double bond(s). Typical alkenyl groups include,but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl,prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl,cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such asbut-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.;and the like.

[0034] “Alkynyl” refers to an unsaturated branched, straight-chain orcyclic alkyl radical having at least one carbon-carbon triple bondderived by the removal of one hydrogen atom from a single carbon atom ofa parent alkyne. Typical alkynyl groups include, but are not limited to,ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.;butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; andthe like.

[0035] “Acyl” refers to a radical —C(O)R, where R is hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl as defined herein. Representative examples include, butare not limited to formyl, acetyl, cyclohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl and the like.

[0036] “Acylamino” refers to a radical —NR′C(O)R, where R′ and R areeach independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein.Representative examples include, but are not limited to, formylamino,acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino,benzoylamino, benzylcarbonylamino and the like.

[0037] “Alkylamino” means a radical —NHR where R represents an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methylamino, ethylamino, 1-methylethylamino,cyclohexyl amino and the like.

[0038] “Alkoxy” refers to a radical —OR where R represents an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy andthe like.

[0039] “Alkoxycarbonyl” refers to a radical —C(O)-alkoxy where alkoxy isas defined herein.

[0040] “Alkylsulfonyl” refers to a radical —S(O)₂R where R is an alkylor cycloalkyl group as defined herein. Representative examples include,but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl,butylsulfonyl and the like.

[0041] “Alkylsulfinyl” refers to a radical —S(O)R where R is an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl,butylsulfinyl and the like.

[0042] “Alkylthio” refers to a radical —SR where R is an alkyl orcycloalkyl group as defined herein that may be optionally substituted asdefined herein. Representative examples include, but are not limited to,methylthio, ethylthio, propylthio, butylthio, and the like.

[0043] “Amino” refers to the radical —NH₂.

[0044] “Aryl” refers to a monovalent aromatic hydrocarbon radicalderived by the removal of one hydrogen atom from a single carbon atom ofa parent aromatic ring system. Typical aryl groups include, but are notlimited to, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene and the like. Preferably, an arylgroup comprises from 6 to 20 carbon atoms, more preferably, between 6 to12 carbon atoms.

[0045] “Arylalkyl” refers to an acyclic alkyl radical in which one ofthe hydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with an aryl group. Typical arylalkyl groupsinclude, but are not limited to, benzyl, 2-phenylethan-1-yl,2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and thelike. Where specific alkyl moieties are intended, the nomenclaturearylalkanyl, arylalkenyl and/or arylalkynyl is used. Preferably, anarylalkyl group is (C₆-C₃₀) arylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the arylalkyl group is (C₁-C₁₀) and the aryl moiety is(C₆-C₂₀), more preferably, an arylalkyl group is (C₆-C₂₀) arylalkyl,e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is(C₁-C₈) and the aryl moiety is (C₆-C₁₂).

[0046] “Arylalkyloxy” refers to an —O-arylalkyl radical where arylalkylis as defined herein.

[0047] “Aryloxycarbonyl” refers to a radical —C(O)—O-aryl where aryl isas defined herein.

[0048] “C₂₃ bile acid moiety” refers to a fragment derived fromnaturally occuring bile acids by removal of the carboxyl group.Preferred C₂₃ bile acid moieties are derived from the followingstructures:

[0049] where R⁴ and R⁵ are both α-OH or R⁴ is β-OH and R⁵ is hydrogen orR⁴ is α-OH and R⁵ is hydrogen or R⁴ is hydrogen and R⁵ is α-OH or R⁴ isβ-OH and R⁵ is α-OH or R⁴ and R⁵ are both hydrogen.

[0050] “Carbamoyl” refers to the radical —C(O)N(R)₂ where each R groupis independently hydrogen, alkyl, cycloalkyl or aryl as defined herein,which may be optionally substituted as defined herein.

[0051] “Carboxy” means the radical —C(O)OH.

[0052] “Cyano” means the radical —CN.

[0053] “Cycloalkyl” refers to a saturated or unsaturated cyclic alkylradical. Where a specific level of saturation is intended, thenomenclature “cycloalkanyl” or “cycloalkenyl” is used. Typicalcycloalkyl groups include, but are not limited to, groups derived fromcyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like. In apreferred embodiment, the cycloalkyl group is (C₃-C₁₀) cycloalkyl, morepreferably (C₃-C₇) cycloalkyl.

[0054] “Cycloheteroalkyl” refers to a saturated or unsaturated cyclicalkyl radical in which one or more carbon atoms (and any associatedhydrogen atoms) are independently replaced with the same or differentheteroatom. Typical heteroatoms to replace the carbon atom(s) include,but are not limited to, N, P, O, S, Si, etc. Where a specific level ofsaturation is intended, the nomenclature “cycloheteroalkanyl” or“cycloheteroalkenyl” is used. Typical cycloheteroalkyl groups include,but are not limited to, groups derived from epoxides, imidazolidine,morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine,quinuclidine, and the like.

[0055] “Cycloheteroalkyloxycarbonyl” refers to a radical —C(O)—OR whereR is cycloheteroalkyl as defined herein.

[0056] “Dialkylamino” means a radical —NRR′ where R and R′ independentlyrepresent an alkyl or cycloalkyl group as defined herein. Representativeexamples include, but are not limited to dimethylamino,methylethylamino, di-(1-methylethyl)amino, (cyclohexyl)(methyl)amino,(cyclohexyl)(ethyl)amino, (cyclohexyl)(propyl)amino, and the like.

[0057] “Derived from a drug” refers to a fragment that is structurallyrelated to such a drug. The structure of the fragment is identical tothe drug except where a hydrogen atom attached to a heteroatom (N or O)has been replaced with a covalent bond to another group (typically, apromoiety). Note that when a drug is a salt form of a carboxylic,phosphonic or phosphoric acid, the corresponding structural fragmentderived from such a drug is considered to derived from the protonatedacid form.

[0058] “Drug” refers to a compound that exhibits therapeutic and/orprophylactic and/or diagnostic utility when administered in effectiveamounts to a mammal.

[0059] “Halo” means fluoro, chloro, bromo, or iodo.

[0060] “Heteroalkyloxy” means an —O-heteroalkyl radical whereheteroalkyl is as defined herein.

[0061] “Heteroalkyl, Heteroalkanyl, Heteroalkenyl, Heteroalkynyl” referto alkyl, alkanyl, alkenyl and alkynyl groups, respectively, in whichone or more of the carbon atoms (and any associated hydrogen atoms) areeach independently replaced with the same or different heteroatomicgroups. Typical heteroatomic groups include, but are not limited to,—O—, —S—, —O—O—, —S—S—, —O—S—, —NR′—, ═N—N═, —N═N—, —N═N—NR′—, —PH—,—P(O)₂—, —O—P(O)₂—, —S(O)—, —S(O)₂—, —SnH₂— and the like, wherein R′ ishydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,aryl or substituted aryl.

[0062] “Heteroaryl” refers to a monovalent heteroaromatic radicalderived by the removal of one hydrogen atom from a single atom of aparent heteroaromatic ring system. Typical heteroaryl groups include,but are not limited to, groups derived from acridine, arsindole,carbazole, ∃-carboline, chromane, chromene, cinnoline, furan, imidazole,indazole, indole, indoline, indolizine, isobenzofuran, isochromene,isoindole, isoindoline, isoquinoline, isothiazole, isoxazole,naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine,phenanthroline, phenazine, phthalazine, pteridine, purine, pyran,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and thelike. Preferably, the heteroaryl group is between 5-20 memberedheteroaryl, with 5-10 membered heteroaryl being particularly preferred.Preferred heteroaryl groups are those derived from thiophene, pyrrole,benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole,oxazole and pyrazine.

[0063] “Heteroaryloxycarbonyl” refers to a radical —C(O)—OR where R isheteroaryl as defined herein.

[0064] “Heteroarylalkyl” refers to an acyclic alkyl radical in which oneof the hydrogen atoms bonded to a carbon atom, typically a terminal orsp³ carbon atom, is replaced with a heteroaryl group. Where specificalkyl moieties are intended, the nomenclature heteroarylalkanyl,heteroarylalkenyl and/or heterorylalkynyl is used. Preferably, theheteroarylalkyl radical is a 6-30 membered heteroarylalkyl, e.g., thealkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-10membered and the heteroaryl moiety is a 5-20 membered heteroaryl, morepreferably, a 6-20 membered heteroarylalkyl, e.g., the alkanyl, alkenylor alkynyl moiety of the heteroarylalkyl is 1-8 membered and theheteroaryl moiety is a 5-12 membered heteroaryl.

[0065] “Hydroxy” means the radical —OH.

[0066] “Oxo” means the divalent radical ═O.

[0067] “Pharmaceutically acceptable” means approved or approvable by aregulatory agency of the Federal or a state government or listed in theU.S. Pharmacopoeia or other generally recognized pharmacopoeia for usein animals, and more particularly in humans.

[0068] “Pharmaceutically acceptable salt” refers to a salt of a compoundof the invention, which is pharmaceutically acceptable and possesses thedesired pharmacological activity of the parent compound. Such saltsinclude: (1) acid addition salts, formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound isreplaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike.

[0069] “Pharmaceutically acceptable vehicle” refers to a diluent,adjuvant, excipient or carrier with which a compound of the invention isadministered.

[0070] “Patient” includes humans. The terms “human” and “patient” areused interchangeably herein.

[0071] “Preventing” or “prevention” refers to a reduction in risk ofacquiring a disease or disorder (i.e., causing at least one of theclinical symptoms of the disease not to develop in a patient that may beexposed to or predisposed to the disease but does not yet experience ordisplay symptoms of the disease).

[0072] “Prodrug” refers to a derivative of a drug molecule that requiresa transformation within the body to release the active drug. Prodrugsare frequently (though not necessarily) pharmacologically inactive untilconverted to the parent drug.

[0073] “Promoiety” refers to a form of protecting group that when usedto mask a functional group within a drug molecule converts the drug intoa prodrug. Typically, the promoiety will be attached to the drug viabond(s) that are cleaved by enzymatic or non-enzymatic means in vivo.

[0074] “Protecting group” refers to a grouping of atoms that whenattached to a reactive group in a molecule masks, reduces or preventsthat reactivity. Examples of protecting groups can be found in Green etal., “Protective Groups in Organic Chemistry”, (Wiley, 2^(nd) ed. 1991)and Harrison et al., “Compendium of Synthetic Organic Methods”, Vols.1-8 (John Wiley and Sons, 1971-1996). Representative amino protectinggroups include, but are not limited to, formyl, acetyl, trifluoroacetyl,benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”),trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl (“SES”), trityland substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl(“NVOC”) and the like. Representative hydroxy protecting groups include,but are not limited to, those where the hydroxy group is either acylatedor alkylated such as benzyl, and trityl ethers as well as alkyl ethers,tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.

[0075] “Racemate” refers to an equimolar mixture of enantiomers of achiral molecule.

[0076] “Substituted” refers to a group in which one or more hydrogenatoms are each independently replaced with the same or differentsubstituent(s). Typical substituents include, but are not limited to,—X, —R⁴, —O⁻, ═O, —OR¹⁴, —SR¹⁴, —S⁻, ═S, —NR¹⁴R¹⁵, ═NR¹⁴, —CX₃, —CF₃,—CN, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)₂O⁻, —S(O)₂OH, —S(O)₂R¹⁴,—OS(O₂)O⁻, —OS(O)₂R¹⁴, —P(O)(O⁻)₂, —P(O)(OR¹⁴)(OR¹⁵), —C(O)R¹⁴,—C(S)R¹⁴, —C(O)OR¹⁴, —C(O)NR¹⁴R¹⁵, —C(O)O⁻, —C(S)OR¹⁴, —NR¹⁶C(O)NR¹⁴R¹⁵,——NR¹⁶C(S)NR¹⁴R¹⁵, —NR¹⁷C(NR¹⁶)NR¹⁴R¹⁵ and —C(NR¹⁶)NR¹⁴R¹⁵, where each Xis independently a halogen; each R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are independentlyhydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl, —NR¹⁸R¹⁹, —C(O)R¹⁸ or —S(O)₂R¹⁸ oroptionally R¹⁸ and R¹⁹ together with the atom to which they are bothattached form a cycloheteroalkyl or substituted cycloheteroalkyl ring;and R¹⁸ and R¹⁹ are independently hydrogen, alkyl, substituted alkyl,aryl, substituted alkyl, arylalkyl, substituted alkyl, cycloalkyl,substituted alkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl or substituted heteroarylalkyl.

[0077] “Thio” means the radical —SH.

[0078] “Treating” or “treatment” of any disease or disorder refers, inone embodiment, to ameliorating the disease or disorder (i.e., arrestingor reducing the development of the disease or at least one of theclinical symptoms thereof). In another embodiment “treating” or“treatment” refers to ameliorating at least one physical parameter,which may not be discernible by the patient. In yet another embodiment,“treating” or “treatment” refers to inhibiting the disease or disorder,either physically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In yet another embodiment, “treating” or “treatment” refers to delayingthe onset of the disease or disorder.

[0079] “Therapeutically effective amount” means the amount of a compoundthat, when administered to a patient for treating a disease, issufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the patientto be treated.

[0080] Reference will now be made in detail to preferred embodiments ofthe invention. While the invention will be described in conjunction withthe preferred embodiments, it will be understood that it is not intendedto limit the invention to those preferred embodiments. To the contrary,it is intended to cover alternatives, modifications, and equivalents asmay be included within the spirit and scope of the invention as definedby the appended claims.

4.2 Compounds of the Invention

[0081] The present invention provides 1-acyl-alkyl derivatives ofstructural Formula (I):

[0082] or a pharmaceutically acceptable salt, hydrate or solvatethereof, wherein:

[0083] n, q, Y, R¹, R², R³, R²¹ and R²² are as defined above.

[0084] Compounds of Formula (I) may be synthetic intermediates in thepreparation of 1-(acyloxy)-alkyl derivatives. Alternatively, compoundsof Formula (I) may be protected versions of drug molecules, where the1-acyl-alkyl portion of the molecule masks a reactive functionality suchas amino group, hydroxyl, etc. Accordingly, compounds of Formula (I) maybe prodrugs of drug molecules and/or may be useful in the synthesis ofnovel drug derivatives.

[0085] In one embodiment, q is 0. In this embodiment, the presentinvention provides 1-acyl-alkyl derivatives of structural Formula (III):

[0086] where n, Y, R¹, R² and R³ are as previously defined. In anotherembodiment, q is 1.

[0087] In one embodiment of compounds of structural Formula (I), R²¹ ishydrogen or alkyl. Preferably, R²¹ is hydrogen, methyl, ethyl, propyl orbutyl, more preferably, R²¹ is hydrogen or methyl.

[0088] In another embodiment of compounds of Formula (I), R²² ishydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl or optionally, together with the carbon atomto which it is attached and the adjacent nitrogen atom forms acycloheteroalkyl or substituted cycloheteroalkyl ring. Preferably, R²²is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl,arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkyl andsubstituted heteroarylalkanyl or optionally, R²² together with thecarbon atom to which it is attached, the adjacent nitrogen atom and R²¹substituent form a cycloheteroalkyl or substituted cycloheteroalkylring.

[0089] In still another embodiment, R²² together with the carbon atom towhich it is attached, the adjacent nitrogen atom and R²¹ form a fivemembered ring. In still another embodiment, R²² is hydrogen,cycloalkanyl or alkanyl. Preferably, R²² is hydrogen, methyl, 2-propyl,2-butyl, isobutyl, t-butyl, cyclopentyl or cyclohexyl.

[0090] In still another embodiment, R²² is substituted alkanyl.Preferably, R²² is —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂,—CH₂CH₂CONH₂, —CH₂CH₂SCH₃, CH₂SH, —CH₂(CH₂)₃NH₂ or —CH₂CH₂CH₂NHC(NH)NH₂.

[0091] In still another embodiment, R²² is selected from the groupconsisting of aryl, arylalkanyl, substituted arylalkanyl andheteroarylalkanyl. Preferably, R²² is phenyl, benzyl, 4-hydroxybenzyl,2-imidazolyl or 2-indolyl.

[0092] In one embodiment, R² and R³ are independently hydrogen, alkyl,substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl,cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substitutedcycloalkoxycarbonyl, heteroaryl or substituted heteroaryl. Preferably,R² and R³ are independently hydrogen, alkyl, alkoxycarbonyl, aryl,arylalkyl, carbamoyl, cycloalkoxycarbonyl or heteroaryl. In oneembodiment, when R² is alkoxycarbonyl, cycloalkoxycarbonyl or carbamoylthen R³ is methyl. More preferably, R¹ and R³ are independentlyhydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, cyclohexyloxycarbonyl, phenyl,benzyl, phenethyl or 3-pyridyl.

[0093] In still another embodiment, R¹ and R³ are independentlyhydrogen, alkanyl or substituted alkanyl. More preferably, R² and R³ arehydrogen or alkanyl. Even more preferably, R² and R³ are independentlyhydrogen, methyl, ethyl, propyl, isopropyl or butyl.

[0094] In still another embodiment, R² and R³ are independentlyhydrogen, aryl, arylalkyl or heteroaryl. More preferably, R¹ and R³ areindependently hydrogen, phenyl, benzyl, phenethyl or 3-pyridyl. Mostpreferably, R² is hydrogen and R³ is hydrogen; R² is methyl and R³ ishydrogen; R² is ethyl and R³ is hydrogen; R¹ is propyl and R³ ishydrogen; R² is isopropyl and R³ is hydrogen; R² is butyl and R³ ishydrogen; R² is phenyl and R³ is hydrogen; R² is methoxycarbonyl and R³is methyl; R² is ethoxycarbonyl and R³ is methyl; R² isisopropoxycarbonyl and R³ is methyl; and R² is methyl and R³ is methyl.

[0095] In still another embodiment, R¹ is hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroarylor a C₂₃ bile acid moiety. Preferably, R¹ is hydrogen, alkyl,substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl. Morepreferably, R¹ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl,phenethyl, styryl or 3-pyridyl.

[0096] In still another embodiment, R¹ is alkanyl or substituted alkanylor a C₂₃ bile acid moiety. More preferably, R¹ is methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl or neopentyl. Most preferably, R¹ is hydrogen, methyl, ethyl,propyl, isopropyl or butyl.

[0097] In still another embodiment, R¹ is hydrogen, aryl, arylalkyl orheteroaryl. More preferably, R¹ is phenyl, 4-methoxyphenyl, benzyl,phenethyl, styryl or 3-pyridyl.

[0098] In still another embodiment, R¹ and either R² or R³, togetherwith the atoms to which R¹ and R² or R³ are attached, form a cycloalkylor substituted cycloalkyl ring, which is optionally fused to an aryl,substituted aryl, heteroaryl or substituted heteroaryl ring. Preferably,R¹ and either R² or R³, together with the atoms to which R¹ and R² or R³are attached, form a cyclobutyl, cyclopentyl or cyclohexyl ring.

[0099] In still another embodiment, R¹ and R³ together with the atom towhich they are attached form a cycloalkyl or substituted cycloalkylring. Preferably, R² and R³ together with the atom to which they areattached form a cyclobutyl, cyclopentyl or cyclohexyl ring.

[0100] In still another embodiment, R¹ is hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,cycloalkyl, substituted cycloalkyl, heteroaryl or substituted heteroaryland R² and R³ are independently hydrogen, alkyl, substituted alkyl,alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substitutedcycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl,heteroaryl or substituted heteroaryl. Preferably, when R² isalkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl then R³ is methyl. Morepreferably, R¹ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl,phenethyl, styryl or 3-pyridyl and R² and R³ are hydrogen, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl,tert-butoxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl or3-pyridyl.

[0101] In still another embodiment, R¹ is hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,cycloalkyl, substituted cycloalkyl, heteroaryl or substituted heteroaryland R² and R³ together with the atom to which they are attached form acycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substitutedcycloheteroalkyl ring. Preferably, R¹ is hydrogen, alkyl, substitutedalkyl, aryl, arylalkyl or heteroaryl and R² and R³ together with theatom to which they are attached form a cycloalkyl or substitutedcycloalkyl ring. More preferably, R¹ is methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl and R² and R³are independently form a cyclobutyl, cyclopentyl or a cyclohexyl ring.

[0102] In still another embodiment, R¹ is alkanyl or substituted alkanyland R² and R³ are independently hydrogen, alkyl, substituted alkyl,alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substitutedcycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl,heteroaryl or substituted heteroaryl. Preferably, R² is alkoxycarbonyl,cycloalkoxycarbonyl or carbamoyl and R³ is methyl. More preferably, R¹is methyl, ethyl, propyl, isopropyl or butyl, and R² and R³ areindependently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl,substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl,cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl orsubstituted heteroaryl. Preferably, R² is alkoxycarbonyl,cycloalkoxycarbonyl or carbamoyl and R³ is methyl.

[0103] In still another embodiment, R¹ is a C₂₃ bile acid moiety and R²and R³ are independently hydrogen, alkyl, substituted alkyl,alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substitutedcycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl,heteroaryl or substituted heteroaryl. Preferably, R² is alkoxycarbonyl,cycloalkoxycarbonyl or carbamoyl and R³ is methyl.

[0104] In still another embodiment, R¹ is hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,cycloalkyl, substituted cycloalkyl, heteroaryl or substituted heteroaryland R² and R³ are independently hydrogen, alkyl, aryl, arylalkyl orheteroaryl. Preferably, R¹ is hydrogen, alkyl, substituted alkyl, aryl,arylalkyl or heteroaryl and R² and R³ are independently hydrogen,alkanyl or substituted alkanyl. Even more preferably, R¹ is hydrogen,alkyl, substituted alkyl, aryl, arylalkyl or heteroaryl and R² and R³are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl or phenyl. Preferably, R¹ is hydrogen,alkyl, substituted alkyl, aryl, arylalkyl or heteroaryl and R² and R³together with the atom to which they are attached form a cycloalkyl,substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkylring. In the above embodiments, R¹ is preferably methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl,styryl or 3-pyridyl.

[0105] In still another embodiment, R¹ is hydrogen, alkyl, substitutedalkyl, aryl, arylalkyl or heteroaryl and R² and R³ are independentlyhydrogen, alkyl, aryl, arylalkyl or heteroaryl. More preferably, R¹ ishydrogen, alkyl, substituted alkyl, aryl, arylalkyl or heteroaryl and R²and R³ are independently hydrogen, alkanyl or substituted alkanyl. Evenmore preferably, R¹ is hydrogen, alkyl, substituted alkyl, aryl,arylalkyl or heteroaryl or substituted cycloalkyl and R² and R³ areindependently hydrogen, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl or phenyl. Preferably, R¹ is hydrogen,alkyl, substituted alkyl, aryl, arylalkyl or heteroaryl and R² and R³together with the atom to which they are attached form a cycloalkyl,substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkylring. In the above embodiments, R¹ is preferably methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl,styryl or 3-pyridyl.

[0106] In still another embodiment, R¹ is alkanyl or substituted alkanyland R² and R³ are independently hydrogen, alkyl, aryl, arylalkyl orcycloalkyl. More preferably, R¹ is alkanyl or substituted alkanyl and R²and R³ are independently hydrogen, alkanyl or substituted alkanyl. Evenmore preferably, R¹ is alkanyl or substituted alkanyl and R² and R³ areindependently hydrogen, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl or phenyl. Preferably, R¹ is alkanyl orsubstituted alkanyl and R² and R³ together with the atom to which theyare attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkylor substituted cycloheteroalkyl ring. In the above embodiments, R¹ ispreferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butylor tert-butyl.

[0107] In still another embodiment, R¹ is a C₂₃ bile acid moiety and R²and R³ are independently hydrogen, alkyl, aryl, arylalkyl or heteroaryl.Preferably, R¹ is a C₂₃ bile acid moiety and R² and R³ are independentlyhydrogen, alkanyl or substituted alkanyl. More preferably, R¹ is a C₂₃bile acid moiety and R² and R³ are independently hydrogen, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl orphenyl. Preferably, R¹ is a C₂₃ bile acid moiety and R² or R³ togetherwith the atom to which they are attached form a cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring.Preferably, in the above embodiments, the C₂₃ bile acid moiety is cholicacid or ursodeoxycholic acid.

[0108] Examples of drugs which contain carboxyl groups (i.e., Y is—C(O)R) include, but are not limited to, angiotensin-converting enzymeinhibitors such as alecapril, captopril,1-[4-carboxy-2-methyl-2R,4R-pentanoyl]-2,3-dihydro-2S-indole-2-carboxylicacid, enalaprilic acid, lisinopril,N-cyclopentyl-N-[3-[(2,2-dimethyl-1-oxopropyl)thio]-2-methyl-1-oxopropyl]glycine,pivopril, quinaprilat,(2R,4R)-2-hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazolidinecarboxylicacid, (S) benzamido-4-oxo-6-phenylhexenoyl-2-carboxypyrrolidine,[2S-1[R*(R*))]] 2α,3α,β7β]-1[2-[[1-carboxy-3-phenylpropyl]-amino]-1-oxopropyl]octahydro-1H-indole-2-carboxylicacid, [3S-1[R*(R*))]],3R*]-2-[2-[[1-carboxy-3-phenylpropyl]-amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinolonecarboxylic acid and tiopronin; cephalosporin antibiotics such ascefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone, cefazuflur,cefazolin, cefbuperazone, cefixime, cefinenoxime, cefinetazole,cefodizime, cefonicid, cefoperazone, ceforamide, cefotaxime, cefotefan,cefotiam, cefoxitin, cefpimizole, cefpirome, cefpodoxime, cefroxadine,cefsulodin, cefpiramide, ceftazidime, ceftezole, ceftizoxime,ceftriaxone, cefuroxime, cephacetrile, cephalexin, cephaloglycin,cephaloridine, cephalosporin, cephanone, cephradine and latamoxef;penicillins such as amoxycillin, ampicillin, apalcillin, azidocillin,azlocillin, benzylpencillin, carbenicillin, carfecillin, carindacillin,cloxacillin, cyclacillin, dicloxacillin, epicillin, flucloxacillin,hetacillin, methicillin, mezlocillin, nafcillin, oxacillin,phenethicillin, piperazillin, sulbenicllin, temocillin and ticarcillin;thrombin inhibitors such as argatroban, melagatran and napsagatran;influenza neuramimidase inhibitors such as zanamivir and BCX-1812;non-steroidal antiinflammatory agents such as acametacin, alclofenac,alminoprofen, aspirin (acetylsalicylic acid), 4-biphenylacetic acid,bucloxic acid, carprofen, cinchofen, cinmetacin, clometacin, clonixin,diclenofac, diflunisal, etodolac, fenbufen, fenclofenac, fenclosic acid,fenoprofen, ferobufen, flufenamic acid, flufenisal, flurbiprofin,fluprofen, flutiazin, ibufenac, ibuprofen, indomethacin, indoprofen,ketoprofen, ketorolac, lonazolac, loxoprofen, meclofenamic acid,mefenamic acid,2-(8-methyl-10,11-dihydro-11-oxodibenz[b,f]oxepin-2-yl)propionic acid,naproxen, nifluminic acid, O-(carbamoylphenoxy)acetic acid, oxoprozin,pirprofen, prodolic acid, salicylic acid, salicylsalicylic acid,sulindac, suprofen, tiaprofenic acid, tolfenamic acid, tolmetin andzopemirac; prostaglandins such as ciprostene,16-deoxy-16-hydroxy-16-vinyl prostaglandin E₂,6,16-dimethylprostaglandin E₂, epoprostostenol, meteneprost, nileprost,prostacyclin, prostaglandins E₁, E₂, or F_(2α) and thromboxane A₂; andquinolone antibiotics such as acrosoxacin, cinoxacin, ciprofloxacin,enoxacin, flumequine, naladixic acid, norfloxacin, ofloxacin, oxolinicacid, pefloxacin, pipemidic acid and piromidic acid; other antibioticssuch as aztreonam, imipenem, meropenem and related carbopenemantibiotics.

[0109] In a preferred embodiment, drugs which contain carboxyl groups(i.e., Y is —C(O)R) include acametacin, argatroban, BCX-140, BCX-1812,cefotaxime, ceftazidime, ceftriaxone, cromolyn, foscarnet, lamifiban,melagatran, meropenem and zanamivir.

[0110] Examples of drugs which contain amine groups (i.e., Y is —NRR′;and the amino fragment may be either primary (i.e., R′ is hydrogen) orsecondary) include, but are not limited to, acebutalol, albuterol,alprenolol, atenolol, bunolol, bupropion, butopamine, butoxamine,carbuterol, cartelolol, colterol, deterenol, dexpropanolol, diacetolol,dobutamine, exaprolol, exprenolol, fenoterol, fenyripol, labotolol,levobunolol, metolol, metaproterenol, metoprolol, nadolol, pamatolol,penbutalol, pindolol, pirbuterol, practolol, prenalterol, primidolol,prizidilol, procaterol, propanolol, quinterenol, rimiterol, ritodrine,solotol, soterenol, sulfiniolol, sulfinterol, sulictidil, tazaolol,terbutaline, timolol, tiprenolol, tipridil, tolamolol, thiabendazole,albendazole, albutoin, alendronate, alinidine, alizapride, amiloride,aminorex, aprinocid, cambendazole, cimetidine, cisapride, clonidine,cyclobenzadole, delavirdine, efegatrin, etintidine, fenbendazole,fenmetazole, flubendazole, fludorex, gabapentin, icadronate,lobendazole, mebendazole, metazoline, metoclopramide, methylphenidate,mexiletine, neridronate, nocodazole, oxfendazole, oxibendazole,oxmetidine, pamidronate, parbendazole, pramipexole, prazosin,pregabalin, procainamide, ranitidine, tetrahydrazoline, tiamenidine,tinazoline, tiotidine, tocainide, tolazoline, tramazoline,xylometazoline, dimethoxyphenethylamine,N-[3(R)-[2-piperidin-4-yl)ethyl]-2-piperidone-1-yl]acetyl-3(R)-methyl-p-alanine,adrenolone, aletamine, amidephrine, amphetamine, aspartame, bamethan,betahistine, carbidopa, clorprenaline, chlortermine, dopamine, L-Dopa,ephrinephrine etryptamine, fenfluramine, methyldopamine, norepinephrine,tocainide, enviroxime, nifedipine, nimodipine, triamterene, pipedemicacid and similar compounds,1-ethyl-6-fluoro-1,4dihydro-4-oxo-7-(1-piperazinyl)-1,8-napthyridine-3-carboxylicacid,1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(piperazinyl)-3-quinolinecarboxylicacid.

[0111] In a preferred embodiment, drugs which contain primary orsecondary amino groups (i.e., Y is —NR′R) include amifostine, baclofen,carbidopa, clonidine, ciprofloxacin, cisapride, daunorubicin,doxorubicin, fenoterol, gabapentin, gentamycin, kanamycin, levodopa,meropenem, metazoline, neomycin, pregabalin, tobramycin, trovafloxacinand vigabatrin.

[0112] Examples of drugs which contain hydroxy groups (i.e., Y is —OR)include, but are not limited to, steroidal hormones such asallylestrenol, cingestol, dehydroepiandrosteron, dienostrol,diethylstilbestrol, dimethisteron, ethyneron, ethynodiol, estradiol,estron, ethinyl estradiol, ethisteron, lynestrenol, mestranol, methyltestosterone, norethindron, norgestrel, norvinsteron, oxogeston,quinestrol, testosteron and tigestol; tranquilizers such as dofexazepam,hydroxyzin, lorazepam and oxazepam; neuroleptics such as acetophenazine,carphenazine, fluphenazine, perphenyzine and piperaetazine; cytostaticssuch as aclarubicin, cytarabine, decitabine, daunorubicin,dihydro-5-azacytidine, doxorubicin, epirubicin, estramustin, etoposide,fludarabine, gemcitabine, 7-hydroxychlorpromazin, nelarabine, neplanocinA, pentostatin, podophyllotoxin, tezacitabine, troxacitabine,vinblastin, vincristin, vindesin; hormones and hormone antagonists suchas buserilin, gonadoliberin, icatibrant and leuprorelin acetate;antihistamines such as terphenadine; analgesics such as diflunisal,naproxol, paracetamol, salicylamide and salicyclic acid; antibioticssuch as azidamphenicol, azithromycin, camptothecin, cefamandol,chloramphenicol, clarithromycin, clavulanic acid, clindamycin,demeclocyclin, doxycyclin, erythromycin, gentamycin, imipenem,latamoxef, metronidazole, neomycin, novobiocin, oleandomycin,oxytetracyclin, tetracycline, thiamenicol and tobramycin; antiviralssuch as acyclovir, d4C, ddC, DMDC, Fd4C, FddC, FMAU, FTC,2′-fluoro-ara-dideoxyinosine, ganciclovir, lamivudine, penciclovir,SddC, stavudine, 5-trifluoromethyl-2′-deoxyuridine, zalcitabine andzidovudine; bisphosphonates such as EB-1053, etidronate, ibandronate,olpadronate, residronate, YH-529 and zolendronate; protease inhibitorssuch as ciprokiren, enalkiren, ritonavir, saquinavir and terlakiren;prostaglandins such as arbaprostil, carboprost, misoprostil andprostacydin; antidepressives such as 8-hydroxychlorimipramine and2-hydroxyimipramine; antihypertonics such as sotarol and fenoldopam;anticholinerogenics such as biperidine, procyclidin and trihexyphenidal;antiallergenics such as cromolyn; glucocorticoids such as betamethasone,budenosid, chlorprednison, clobetasol, clobetasone, corticosteron,cortisone, cortodexon, dexamethason, flucortolon, fludrocortisone,flumethasone,flunisolid, fluprednisolon, flurandrenolide, flurandrenolonacetonide, hydrocortisone, meprednisone, methylpresnisolon,paramethasone, prednisolon, prednisol, triamcinolon and triamcinolonacetonide; narcotic agonists and antagonists such as apomorphine,buprenorphine, butorphanol, codein, cyclazocin, hydromorphon,ketobemidon, levallorphan, levorphanol, metazocin, morphine, nalbuphin,nalmefen, naloxon, nalorphine, naltrexon, oxycodon, oxymorphon andpentazocin; stimulants such asmazindol and pseudoephidrine; anaestheticssuch as hydroxydion and propofol; β-receptor blockers such asacebutolol, albuterol, alprenolol, atenolol, betazolol, bucindolol,cartelolol, celiprolol, cetamolol, labetalol, levobunelol, metoprolol,metipranolol, nadolol, oxyprenolol, pindolol, propanolol and timolol;α-sympathomimetics such as adrenalin, metaraminol, midodrin,norfenefrin, octapamine, oxedrin, oxilofrin, oximetazolin andphenylefrin; β-sympathomimetics such as bamethan, clenbuterol,fenoterol, hexoprenalin, isoprenalin, isoxsuprin, orciprenalin,reproterol, salbutamol and terbutalin; bronchodilators such ascarbuterol, dyphillin, etophyllin, fenoterol, pirbuterol, rimiterol andterbutalin; cardiotonics such as digitoxin, dobutamin, etilefrin andprenalterol; antimycotics such as amphotericin B, chlorphenesin,nystatin and perimycin; anticoagulants such as acenocoumarol,dicoumarol, phenprocoumon and warfarin; vasodilators such as bamethan,dipyrimadol, diprophyllin, isoxsuprin, vincamin and xantinol nicotinate;antihypocholesteremics such as compactin, eptastatin, mevinolin andsimvastatin; and miscellaneous drugs such as bromperidol(antipsychotic), dithranol (psoriasis) ergotamine (migraine) ivermectin(antihelminthic), metronidazole and secnizadole (antiprotozoals),nandrolon (anabolic), propafenon and quinadine (antiarythmics),quetiapine (CNS), serotonin (neurotransmitter) and silybin (hepaticdisturbance).

[0113] In a preferred embodiment, drugs which contain hydroxyl groups(i.e., Y is —OR) include adenosine, cromolyn, cytarabine, decitabine,didanosine, docetaxel, gemcitabine, norgestrel, paclitaxel, pentostatinand vinblastine.

[0114] Examples of drugs which contain phosphonic acid or phosphonatemoieties (i.e., Y is —P(O)(OR′)R; and R′ may be hydrogen) include, butare not limited to, adefovir, alendronate, AR-C69931MX, BMS-187745,ceronapril, CGP-24592, CGP-37849, CGP-39551, CGP-40116, cidofovir,clodronate, EB-1053, etidronate, fanapanel, foscamet, fosfomycin,fosinopril, fosinoprilat, ibandronate, midafotel, neridronate,olpadronate, pamidronate, residronate, tenofovir, tiludronate,WAY-126090, YH-529 and zolendronate.

[0115] In a preferred embodiment, drugs which contain phosphonic acid orphosphonate moieties (i.e., Y is —P(O)(OR)R′) include alendronate,cidofovir, clodronate, foscarnet, ibandronate, midafotel, olpadronate,pamidronate, residronate and zoledronate.

[0116] Examples of drugs which contain phosphoric acid or phosphatemoieties (i.e., Y is —P(O)(OR)(OR′); and R′ may be hydrogen) include,but are not limited to, bucladesine, choline alfoscerate, citocoline,fludarabine phosphate, fosopamine, GP-668, perifosine, triciribinephosphate and phosphate derivatives of nucleoside analogs which requirephophorylation for activity, such as 3TC, acyclovir, AZT, BVDU, ddC,ddI, FMAU, FTC, ganciclovir, gemcitabine, H2G, lamivudine, penciclovirand the like.

[0117] In a preferred embodiment, drugs which contain phosphoric acid orphosphate moieties (i.e., Y is —P(O)(OR)(OR′)) include bucladesine,choline alfoscerate, citocoline, fludarabine phosphate, fosopamine,GP-668, perfosine and triciribine.

[0118] The above examples of drug compounds are merely representativerather than comprehensive. Accordingly, given the teachings above, theskilled artisan may be able to identify drug molecules other than thoselisted above which may be converted to a 1-acyl-alkyl derivative.

[0119] Preferably, the compounds of structural Formula (I) have thestructure of Formulae (IV) and (V), illustrated below. Here, Y is —NRR′and HNRR′ is

[0120] gabapentin and esters or thioesters thereof or pregabalin andesters or thioesters thereof. In Formulae (IV) and (V), X is O or S andR²⁰ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl, while q, R¹, R², R³, R²¹ and R²² are aspreviously defined.

[0121] In one embodiment of compounds of Formulae (IV) and (V), R²⁰ isselected from the group consisting of hydrogen, alkyl, substituted alkylaryl, substituted aryl, arylalkanyl, substituted arylalkanyl,cycloalkanyl, substituted cycloalkanyl, cycloheteroalkanyl andsubstituted cycloheteroalkanyl. In a preferred embodiment, X is O andR²⁰ is hydrogen. In still another embodiment, X is o and R²⁰ is alkanyl,substituted alkanyl, alkenyl, substituted alkenyl, aryl or substitutedaryl. Preferably, R²⁰ is —C(CH₃)═CH₂, —CH₂C(═O)N(CH₃)₂, 4-fluorophenylor

[0122] In one preferred embodiment of Formulae (IV) and (V), q is 0. Inanother preferred embodiment of Formulae (IV) and (V), q is 1.

[0123] In another embodiment of compounds of structural Formulae (IV)and (V), R²¹ is hydrogen or alkyl. Preferably, R²² is hydrogen, methyl,ethyl, propyl or butyl, more preferably, R²¹ is hydrogen or methyl.

[0124] In still another embodiment of compounds of Formulae (IV) and(V), R²² is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl or optionally, R²² together with the carbonatom to which it is attached, the adjacent nitrogen atom and R²¹substituent form a cycloheteroalkyl or substituted cycloheteroalkylring. Preferably, R²² is hydrogen, alkanyl, substituted alkanyl, aryl,substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl,heteroarylalkyl and substituted heteroarylalkanyl or optionally, R²²together with the carbon atom to which it is attached, the adjacentnitrogen atom and R²¹ substituent form a cycloheteroalkyl or substitutedcycloheteroalkyl ring.

[0125] In still another embodiment of compounds of Formulae (IV) and(V), R²² together with the carbon atom to which it is attached, theadjacent nitrogen atom and R²¹ substituent form a five membered ring. Inanother embodiment, R²² is hydrogen, cycloalkanyl or alkanyl.Preferably, R²² is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl,t-butyl, cyclopentyl or cyclohexyl.

[0126] In still another embodiment of compounds of Formulae (IV) and(V), R²² is substituted alkanyl. Preferably, R²² is —CH₂OH, —CH(OH)CH₃,—CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, CH₂SH,—CH₂(CH₂)₃NH₂ or —CH₂CH₂CH₂NHC(NH)NH₂.

[0127] In still another embodiment of compounds of Formulae (IV) and(V), R²² is selected from the group consisting of aryl, arylalkanyl,substituted arylalkanyl and heteroarylalkanyl. Preferably, R²² isphenyl, benzyl, 4-hydroxybenzyl, 2-imidazolyl or 2-indolyl.

[0128] In still another embodiment of compounds of Formulae (IV) and(V), q is 1, R²¹ is hydrogen and R²² is phenyl, benzyl, 4-hydroxybenzyl,2-imidazolyl, 2-indolyl, CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H,—CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, CH_(2S)H, —CH₂(CH₂)₃NH₂,—CH₂CH₂CH₂NHC(NH)NH₂, hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, orR²² together with the carbon atom to which it is attached, the adjacentnitrogen atom and R²¹ substituent form a five membered ring.

[0129] In still another embodiment of compounds of Formulae (IV) and(V), R² and R³ are independently hydrogen, alkyl, substituted alkyl,alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substitutedcycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl,heteroaryl or substituted heteroaryl. Preferably, R² and R³ areindependently hydrogen, alkyl, alkoxycarbonyl, aryl, arylalkyl,carbamoyl, cycloalkoxycarbonyl or heteroaryl. Preferably, when R² isalkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl then R³ is methyl. Morepreferably, R² and R³ are independently hydrogen, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl,cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl or 3-pyridyl.

[0130] In still another embodiment of compounds of Formulae (IV) and(V), R² and R³ are independently hydrogen, alkanyl or substitutedalkanyl. Preferably, R² and R³ are hydrogen or alkanyl. More preferably,R² and R³ are independently hydrogen, methyl, ethyl, propyl, isopropylor butyl.

[0131] In still another embodiment of compounds of Formulae (IV) and(V), R² and R³ are independently hydrogen, aryl, arylalkyl orheteroaryl. Preferably, R² and R³ are independently hydrogen, phenyl,benzyl, phenethyl or 3-pyridyl. More preferably, R² is hydrogen and R ishydrogen; R² is methyl and R³ is hydrogen; R² is ethyl and R³ ishydrogen; R² is propyl and R³ is hydrogen; R² is isopropyl and R³ ishydrogen; R² is butyl and R³ is hydrogen; R² is phenyl and R ishydrogen; R is methoxycarbonyl and R 3 is methyl; R² is ethoxycarbonyland R³ is methyl; R² is isopropoxycarbonyl and R³ is methyl; R² ismethyl and R³ is methyl.

[0132] In still another embodiment of compounds of Formulae (IV) and(V), R¹ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl or a C₂₃ bile acid moiety.Preferably, R¹ is hydrogen, alkyl, substituted alkyl, aryl, arylalkyl,cycloalkyl or heteroaryl. More preferably, R¹ is methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl.

[0133] In still another embodiment of compounds of Formulae (IV) and(V), R¹ is alkanyl or substituted alkanyl or a C₂₃ bile acid moiety.Preferably, R¹ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl or neopentyl. Morepreferably, R¹ is hydrogen, methyl, ethyl, propyl, isopropyl or butyl.

[0134] In still another embodiment of compounds of Formulae (IV) and(V), R¹ is cycloalkyl or substituted cycloalkyl. Preferably, R¹ iscyclobutyl, cyclopentyl or cyclohexyl.

[0135] In still another embodiment of compounds of Formulae (IV) and(V), R¹ is hydrogen, aryl, arylalkyl or heteroaryl. Preferably, R¹ isphenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl.

[0136] In still another embodiment of compounds of Formulae (IV) and(V), R¹ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl or3-pyridyl, R² is hydrogen and R³ is hydrogen. In still anotherembodiment, R¹ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,benzyl or 3-pyridyl, R² is methyl and R³ is hydrogen. In still anotherembodiment, R¹ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,benzyl or 3-pyridyl, R² is ethyl and R³ is hydrogen. In still anotherembodiment, R¹ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,benzyl or 3-pyridyl, R² is propyl and R³ is hydrogen. In still anotherembodiment, R¹ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,benzyl or 3-pyridyl, R² is isopropyl and R³ is hydrogen. In stillanother embodiment, R¹ is methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl,phenyl, benzyl or 3-pyridyl, R² is butyl and R³ is hydrogen. In stillanother embodiment, R¹ is methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl,phenyl, benzyl or 3-pyridyl, R² is isobutyl and R³ is hydrogen. In stillanother embodiment, R¹ is methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl,phenyl, benzyl or 3-pyridyl, R² is sec-butyl and R³ is hydrogen. Instill another embodiment, R¹ is methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl,phenyl, benzyl or 3-pyridyl, R² is tert-butyl and R³ is hydrogen. Instill another embodiment, R¹ is methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl,phenyl, benzyl or 3-pyridyl, R² is phenyl and R³ is hydrogen.

[0137] In still another embodiment of compounds of Formulae (IV) and(V), R¹ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl or3-pyridyl, R² is methyl and R is methyl. In still another embodiment, R¹is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl or3-pyridyl, R² is methoxycarbonyl and R³ is methyl. In still anotherembodiment, R¹ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,benzyl or 3-pyridyl, R² is ethoxycarbonyl and R³ is methyl. In stillanother embodiment, R¹ is methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl,phenyl, benzyl or 3-pyridyl, R¹ is isopropoxycarbonyl and R³ is methyl.In still another embodiment, R¹ is methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclopentyl,cyclohexyl, phenyl, benzyl or 3-pyridyl, R² is cyclohexyloxycarbonyl andR³ is methyl.

[0138] In still another embodiment of compounds of Formulae (IV) and(V), R¹ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl or3-pyridyl and R² and R³ together with the atom to which they areattached form a cyclohexyl ring. In still another embodiment, R¹ and R²form a cyclobutyl ring, a cyclopentyl ring or cyclohexyl ring and R³ ishydrogen. In still another embodiment, R¹ and R² form a cyclobutyl ring,a cyclopentyl ring or cyclohexyl ring and R³ is methyl.

[0139] In still another embodiment of compounds of Formulae (IV) and(V), q is 0 or 1.

4.3 Synthesis of the Compounds of the Invention

[0140] The compounds of the invention may be obtained via the syntheticmethods illustrated in Schemes 1-7. Starting materials useful forpreparing compounds of the invention and intermediates thereof (i.e.,α-hydroxy ketones) are commercially available or can be prepared bywell-known synthetic methods (See, e.g., Tetrahedron Lett. 1990, 31,2599; Tetrahedron Lett. 1997, 31, 7183). Other methods for synthesis ofthe compounds described herein and/or starting materials are eitherdescribed in the art or will be readily apparent to the skilled artisanin view of general references well-known in the art (See e.g., Green etal., “Protective Groups in Organic Chemistry”, (Wiley, 2^(nd) ed. 1991);Harrison et al., “Compendium of Synthetic Organic Methods”, Vols. 1-8(John Wiley and Sons, 1971-1996); “Beilstein Handbook of OrganicChemistry,” Beilstein Institute of Organic Chemistry, Frankfurt,Germany; Feiser et al, “Reagents for Organic Synthesis,” Volumes 1-17,Wiley Interscience; Trost et al., “Comprehensive Organic Synthesis,”Pergamon Press, 1991; “Theilheimer's Synthetic Methods of OrganicChemistry,” Volumes 1-45, Karger, 1991; March, “Advanced OrganicChemistry,” Wiley Interscience, 1991; Larock “Comprehensive OrganicTransformations,” VCH Publishers, 1989; Paquette, “Encyclopedia ofReagents for Organic Synthesis,” John Wiley & Sons, 1995) and may beused to synthesize the compounds of the invention. Accordingly, themethods presented in the Schemes herein are illustrative rather thancomprehensive.

[0141] Reaction of hydroxyketone 101 (either commercially available orprepared by procedures known to the skilled artisan) as illustrated inScheme 1 and drug derivatives such as isocyanate 103, haloformate 105(or synthetic equivalent such as a p-nitrophenyl carbonate derivative),acid halide 107 (or synthetic equivalent such as anhydrides ofcarboxylic acids, active esters, etc.), phosphonyl halide 109 (orsynthetic equivalent such as active esters) or phosphoryl halide 111 (orsynthetic equivalent such as active esters) provides ketocarbamate 134,ketocarbonate 115, ketoester 117, ketophosphonate 119 or ketophosphate121, respectively. Methods for preparing the drug derivatives (i.e.,derivatives 103, 105, 107, 109 and 111) and procedures for convertingthe reactants to products are well-known to the skilled artisan.

[0142] Another procedure for synthesizing compounds 117, 119 and 121 isillustrated in Scheme 2.

[0143] Haloketone 123, (X=halide, preferably either R² or R³ ishydrogen) which may be prepared by methods known to the skilled artisan,may be reacted with drugs such as carboxylic acid 125, phosphonate 127or phosphate 129 to provide ketoester 117, ketophosphonate 119 andketophosphate 121, respectively. Preferably, the reactions illustratedabove are conducted in the presence of base (e.g., cesium carbonate,silver carbonate or silver oxide) in an appropriate solvent (e.g.,dimethylformamide or hexamethyphosphoramide). Other procedures foreffecting the transformations illustrated above will be apparent tothose of skill in the art.

[0144] Another method, which is analogous to the processes depicted inScheme 2, is illustrated in Scheme 3. Amine drug 131 may be carbonylatedto provide carbamic acid 133 which may be reacted with haloketone 123 inthe presence of base (e.g., cesium carbonate, silver carbonate or silveroxide) in an appropriate solvent (e.g., dimethylformamide orhexamethyphosphoramide) to yield ketocarbamate 113.

[0145] Another method, which may be used to synthesize ketocarbamate 113and ketocarbonate 115, is illustrated in Scheme 4. Hydroxyketone 101 maybe reacted with phosgene or synthetic equivalent 135 (e.g., triphosgene,carbonyldiimidazole, p-nitrophenylchloroformate, etc.) to provideactivated derivative 136 (Y leaving group), which upon treatment withalcohol drug 137 or amine drug 131 is converted to ketocarbonate 115 orketocarbamate 113, respectively.

[0146] Propargylic alcohol derivatives may be used to synthesizeketocarbamate 146, ketocarbonate 148, ketoester 150, ketophosphonate 152or ketophosphate 154. Illustrated in Scheme 5, and well-known to thoseof skill in the art, nucleophilic addition of alkynyl organometallicreagent 139 to aldehyde or ketone 141 provides propargylic alcohol 143.

[0147] As illustrated in Scheme 6, propargylic alcohol 143 may beconverted to propargylic carbamate 145, propargylic carbonate 147,propargylic ester 149, propargylic phosphonate 151 or propargylicphosphate 153 using, for example, the methods shown in Scheme 1 orScheme 4. Propargylic carbamate 145, propargylic carbonate 147,propargylic ester 149, propargylic phosphonate 151 or propargylicphosphate 153 may be transformed to ketocarbamate 146, ketocarbonate148, ketoester 150, ketophosphonate 152 or ketophosphate 154,respectively, for example, by oxymercuration (e.g., HgO or HgSO₄ in thepresence of water).

[0148] As illustrated in Scheme 7, diazoketone 155 may be reacted withcarboxylic acid 125, phosphonate 127, or phosphate 129 to provideketoester 117, ketophosphonate 119 or ketophosphate 121, respectively(R³ is hydrogen in Scheme 7, below). Preferably, the reactionillustrated above is carried out in the presence of a metal catalyst(e.g., Rh₂(OAc)₄).

[0149] Those of skill in the art will appreciate that compounds ofFormula (I) where q is 1 may be synthesized simply by first acylating anamino or hydroxyl drug (i.e., NHRR′ and HOR, respectively) with asuitably protected amino acid, followed by deprotection to generate afree amine (See, e.g., Bodanszky, “Principles of Peptide Synthesis,Springer-Verlag, 1984; Bodanszky et al., “The Practice of PeptideSynthesis, Springer-Verlag, 1984). The free amine may be converted to acompound of Formula (I), for example, by methods illustrated in Schemes1-4 and 6.

4.4 Methods for Synthesis of Prodrugs From 1-(Acyl)-Alkyl Derivatives

[0150] Generally, the present invention provides methods for synthesisof 1-(acyloxy)-alkyl derivatives. Preferably, 1-(acyloxy)-alkylderivatives are synthesized by oxidation of 1-acyl-alkyl derivatives.More preferably, 1-(acyloxy)-alkyl derivatives of pharmacologicallyeffective drugs are synthesized by oxidation of 1-acyl-alkyl derivativesof pharmacologically effective drugs.

[0151] In a preferred embodiment, the method of the current inventionoxidizes a 1-acyl-alkyl derivative of structural Formula (I) to a1-(acyloxy)-alkyl derivative of structural Formula (II), as shown inScheme 8 below, where R¹, R², R³, R²¹, R²², Y, q and n are defined asdescribed in Section 4.2, herein. Preferred embodiments of R¹, R², R³,R²¹, R²², Y, q and n for compounds of structural Formula (I) andstructural Formula (II) individually or in combination, are alsodescribed in Section 4.2, herein.

[0152] Particularly preferred 1-(acyloxy)-alkyl derivatives include1-acyl-alkoxycarbonyl derivatives of gabapentin, esters and thioestersthereof or pregabalin, esters and thioesters thereof in Formulae (VI)and (VII) respectively, where R¹, R², R³, R²⁰, R²¹, R²², Y, X, q and nare defined as described in Section 4.2, herein.

[0153] Preferred embodiments of R¹, R², R³, R²⁰, R²¹, R²², Y, X, q andn, individually or in combination for compounds of Formulae (VI) or(VII) have also been described in Section 4.2, herein.

[0154] Preferably, the oxidation of a compound of structural Formula (I)to a compound of structural Formula (II) is performed in the liquidphase, more preferably, in the presence of a solvent. Choosing a solventfor oxidation of a compound of structural Formula (I) is well within theambit of one of skill in the art. Generally, a preferred solvent willdissolve, at least partially, both the oxidant and the compound ofstructural Formula (I) and will be inert to the reaction conditions.Preferred solvents include, but are not limited to, t-butanol,diethylether, acetic acid, hexane, dichloroethane, dichloromethane,ethyl acetate, acetonitrile, methanol, chloroform and water. As isobvious to the skilled artisan, mixtures of the above solvents may alsobe used in the oxidation of a compound of structural Formula (I) to acompound of structural Formula (II).

[0155] Generally, an oxidant may be an organism (e.g., yeast orbacteria), or a chemical reagent (e.g., an enzyme or peroxide) which canconvert a compound of structural Formula (I) to a compound of structuralFormula (II). Preferred oxidants include those, which have beensuccessfully used in Baeyer-Villager oxidations of ketones to esters orlactones (Strukul, Angnew. Chem. Int. Ed., 1998, 37, 1198; Renz et al.,Eur. J. Org. Chem. 1999, 737; Beller et al., in “Transitions Metals inOrganic Synthesis” Chapter 2, Wiley VCH; Stewart, Current OrganicChemistry, 1998, 2, 195; Kayser et al., Synlett, 1999, 1, 153).

[0156] In one embodiment, the oxidant is yeast (e.g., Saccharomycescerevisiae) or bacteria (e.g., Acinetobacter sp. NCIB 9871). In anotherembodiment, the oxidant is a peroxide (preferably, H₂O₂, t-BuOOH or(TMS)₂O₂) or a peroxyacid (preferably, CF₃CO₃H, MeCO₃H, mCPBA,monopermaleic acid, mono-o-perphthalic acid, 3,5 dinitroperbenzoic acid,o-nitroperbenzoic acid, m-nitroperbenzoic acid, p-nitroperbenzoic acid,performic acid, perbenzoic acid, persulfuric acid, or a salt thereof).In still another embodiment, the oxidant is an enzyme and oxygen.Preferably, the enzyme is cyclohexanone monooxygenase.

[0157] In a preferred embodiment, a transition metal complex may becontacted with a peroxide or peroxy acid prior to reaction with acompound of Formula (I). Preferably, the transition metal complexesinclude, but are not limited, to those illustrated below:

[0158] While not wishing to be bound by theory, the transition metalcomplex may react with the peroxide or peroxy acid to form a newoxidant, which may be more active than the parent oxidant.

[0159] Further, the use of additives in the oxidation of a compound ofstructural Formula (I) to a compound of structural Formula (II) is alsocontemplated. While not wishing to be bound by theory, additives mayeither catalyze the reaction or stabilize the final product or both.

[0160] Preferably the molar ratio of oxidant to the compound of Formula(I) is between 8:1 and 1:1. More preferably the molar ratio of oxidantto the compound of Formula (I) is between 4:1 and 1:1. Even morepreferably the molar ratio of oxidant to the compound of Formula (I) isbetween 2:1 and 1:1. Still more preferably, when the oxidant isperbenzoic acid or a substituted perbenzoic acid, the molar ratio ofoxidant to the compound of Formula (1) is 2:1. The entire quantity ofoxidant may either be added to the compound of Formula (I) in oneportion or in several portions. Typically, when a large excess ofoxidant is used relative to the compound of Formula (I), the oxidant isadded in several portions.

[0161] In a preferred embodiment, a Lewis acid or a protic acid or anycombination of Lewis acid or protic acid may be used in the oxidation ofa compound of structural Formula (1) (preferably, in the presence of asolvent). Preferred Lewis acids include, but are not limited to, BF₃,SeO₂, MeReO₃, MnO₂, SnCl₄, Sc(OTf)₃, Ti(O-iPr)₄, Al₂O₃ and Fe₂O₃.

[0162] Preferred protic acids include, but are not limited to, aceticacid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroaceticacid, trifluoromethanesulfonic acid, hydrochloric acid and sulfuricacid. While not wishing to be bound by theory, the Lewis acid and/orprotic acid may catalyze oxidation by increasing the electrophilicity ofthe carbonyl group in structural Formula (I).

[0163] In another preferred embodiment, the oxidation may be conductedin the presence of a base, which is preferably a buffer. Preferred basesinclude, but are not limited to, Na₂HPO₄, K₂HPO₄, NaHCO₃, Na₂CO₃ andLi₂CO₃. While not wishing to be bound by theory, the base may stabilizeacid sensitive products by reacting with acidic by-products formedduring oxidation.

[0164] Generally, the temperature of the oxidation may be readilyoptimized by methods known to those of ordinary skill in the art.Preferably, the oxidation of a compound of Formula (I) is carried out ata temperature between about −25° C. and about 120° C. (more preferably,between about 0° C. and about 25° C.).

[0165] A particularly advantageous feature of this method of synthesisof 1-(acyloxy)-alkyl derivatives (II) is that the oxidation of1-acyl-alkyl derivatives (I) proceeds stereospecifically, with retentionof configuration at the carbon atom initially adjacent to the carbonylgroup in hydroxyketone (I). This may be exploited in a non-racemicsynthesis of 1-(acyloxy)-alkyl prodrug derivatives, as illustrated inScheme 9 with the synthesis of1-{[(α-(S)-isobutanoyloxyisobutoxy)carbonyl]-aminomethyl}-1-cyclohexaneacetic acid and1-{[(α-(R)-isobutanoyloxyisobutoxy)-carbonyl]aminomethyl}-1-cyclohexaneacetic acid, 181 and 183. In this synthesis the chiral building blocks(S)-2-hydroxy-3-methylbutyric acid 157 and (R)-2-hydroxy-3-methylbutyricacid 159 are converted to the chiral α-hydroxyketones 173 and 175respectively. Activation of these synthons as their p-nitrophenylcarbonates and reaction with gabapentin affords the carbamates 177 and179. Oxidation with mCPBA provides the enantiomericacyloxyalkylcarbamate prodrugs 181 and 183.

4.5 Therapeutic Uses of Compounds of Structural Formulae (IV), (V), (VI)and (VII)

[0166] In accordance with the invention, a compound and/or a compositioncontaining a compound of structural Formulae (IV), (V), (VI) or (VII) isadministered to a patient, preferably a human, suffering from epilepsy,depression, anxiety, psychosis, faintness attacks, hypokinesia, cranialdisorders, neurodegenerative disorders, panic, pain (especially,neuropathic pain and muscular and skeletal pain), inflammatory disease(i.e., arthritis), insomnia, gastrointestinal disorders or ethanolwithdrawal syndrome. Further, in certain embodiments, the compoundsand/or compositions of the invention are administered to a patient,preferably a human, as a preventative measure against various diseasesor disorders. Thus, the compounds and/or compositions containingcompound(s) of structural Formulae (IV), (V), (VI) or (VII) may beadministered as a preventative measure to a patient having apredisposition for epilepsy, depression, anxiety, psychosis, faintnessattacks, hypokinesia, cranial disorders, neurodegenerative disorders,panic, pain (especially, neuropathic pain and muscular and skeletalpain), inflammatory disease (i.e., arthritis), insomnia,gastrointestinal disorders and ethanol withdrawal syndrome. Accordingly,the compounds and/or compositions containing compound(s) of structuralFormulae (IV), (V), (VI) or (VII) be used for the prevention of onedisease or disorder and concurrently treating another (e.g., preventionof psychosis while treating gastrointestinal disorders; prevention ofneuropathic pain while treating ethanol withdrawal syndrome).

[0167] The suitability of the compounds and/or compositions containingcompound(s) of structural Formulae (IV), (V), (VI) or (VII) in treatingepilepsy, depression, anxiety, psychosis, faintness attacks,hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain(especially neuropathic pain and muscular and skeletal pain),inflammatory disease (i.e., arthritis), insomnia, gastrointestinaldisorders and ethanol withdrawal syndrome may be determined by methodsdescribed in the art (See, e.g., Satzinger et al., U.S. Pat. No.4,024,175; Satzinger et al., U.S. Pat. No. 4,087,544; Woodruff, U.S.Pat. No. 5,084,479; Silverman et al., U.S. Pat. No. 5,563,175; Singh,U.S. Pat. No. 6,001,876; Horwell et al., U.S. Pat. No. 6,020,370;Silverman et al., U.S. Pat. No. 6,028,214; Horwell et al., U.S. Pat. No.6,103,932; Silverman et al., U.S. Pat. No. 6,117,906; Silverman,International Publication No. WO 92/09560; Silverman et al.,International Publication No. WO 93/23383; Horwell et al., InternationalPublication No. WO 97/29101, Horwell et al., International PublicationNo. WO 97/33858; Horwell et al., International Publication No. WO97/33859; Bryans et al., International Publication No. WO 98/17627;Guglietta et al., International Publication No. WO 99/08671; Bryans etal., International Publication No. WO 99/21824; Bryans et al.,International Publication No. WO 99/31057; Magnus-Miller et al.,International Publication No. WO 99/37296; Bryans et al., InternationalPublication No. WO 99/31075; Bryans et al., International PublicationNo. WO 99/61424; Pande, International Publication No. WO 00/23067;Bryans, International Publication No. WO 00/31020; Bryans et al.,International Publication No. WO 00/50027; Bryans et al, InternationalPublication No. WO 02/00209; Gallop et al., U.S. patent application Ser.No. ______). The compounds and/or compositions of the invention may beused to treat epilepsy, depression, anxiety, psychosis, faintnessattacks, hypokinesia, cranial disorders, neurodegenerative disorders,panic, pain (especially neuropathic pain and muscular and skeletalpain), inflammatory disease (i.e., arthritis), insomnia,gastrointestinal disorders and ethanol withdrawal syndrome y proceduresdescribed in the art (see references above). Thus, those of skill in theart may readily assay and use the compounds and/or compositionscontaining compound(s) of structural Formulae (IV), (V), (VI) or (VII)to treat epilepsy, depression, anxiety, psychosis, faintness attacks,hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain(especially, neuropathic pain and muscular and skeletal pain),inflammatory disease (i.e., arthritis), insomnia, gastrointestinaldisorders and ethanol withdrawal syndrome.

4.6 Therapeutic/Prophylactic Administration

[0168] The compounds, and/or compositions containing compound(s), ofstructural Formulae (IV), (V), (VI) or (VII) may be advantageously usedin human medicine. As previously described in Section 4.5 above,compounds and compositions containing compound(s) of structural Formulae(IV), (V), (VI) or (VII) are useful for the treatment or prevention ofepilepsy, depression, anxiety, psychosis, faintness attacks,hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain(especially, neuropathic pain and muscular and skeletal pain),inflammatory disease (i.e., arthritis), insomnia, gastrointestinaldisorders or ethanol withdrawal syndrome.

[0169] When used to treat or prevent the above disease or disorderscompounds and/or compositions of the invention may be administered orapplied singly, in combination with other agents. The compounds and/orcompositions of the invention may also be administered or appliedsingly, in combination with other pharmaceutically active agents,including other compounds and/or compositions of the invention.

[0170] The current invention provides methods of treatment andprophylaxis by administration to a patient of a therapeuticallyeffective amount of a composition and/or compound of the invention. Thepatient may be an animal, is more preferably a mammal, and mostpreferably a human.

[0171] The present compounds and/or compositions of the invention, whichcomprise one or more compounds and/or compositions of the invention arepreferably administered orally. The compounds and/or compositions of theinvention may also be administered by any other convenient route, forexample, by infusion or bolus injection, by absorption throughepithelial or mucocutaneous linings (e.g., oral mucosa, rectal andintestinal mucosa, etc.). Administration can be systemic or local.Various delivery systems are known, (e.g., encapsulation in liposomes,microparticles, microcapsules, capsules, etc.) that can be used toadminister a compound and/or composition of the invention. Methods ofadministration include, but are not limited to, intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, intranasal, intracerebral, intravaginal,transdermal, rectally, by inhalation, or topically, particularly to theears, nose, eyes, or skin.

[0172] In particularly preferred embodiments, the compounds and/orcompositions of the invention can be delivered via sustained releasesystems, preferably oral sustained release systems. In one embodiment, apump may be used (See, Langer, supra; Sefton, 1987, CRC Crit. RefBiomed. Eng. 14:201; Saudek et al., 1989, N. Engl. J Med. 321:574).

[0173] In another embodiment, polymeric materials can be used (see“Medical Applications of Controlled Release,” Langer and Wise (eds.),CRC Pres., Boca Raton, Fla. (1974); “Controlled Drug Bioavailability,”Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, NewYork (1984); Ranger and Peppas, 1983, J Macromol. Sci. Rev. MacromolChem. 23:61; see also Levy et al., 1985, Science 228: 190; During etal., 1989, Ann. Neurol. 25:351; Howard et al, 1989, J. Neurosurg.71:105). In a preferred embodiment, polymeric materials are used fororal sustained release delivery. Preferred polymers include sodiumcarboxymethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose and hydroxyethylcellulose (most preferred,hydroxypropylmethylcellulose). Other preferred cellulose ethers havebeen described (Alderman, Int. J. Pharm. Tech. & Prod. Mfr., 1984, 5(3)1-9). Factors affecting drug release are well known to the skilledartisan and have been described in the art (Bamba et al., Int. J.Pharm., 1979, 2, 307).

[0174] In another embodiment, enteric-coated preparations can be usedfor oral sustained release administration. Preferred coating materialsinclude polymers with a pH-dependent solubility (i.e., pH-controlledrelease), polymers with a slow or pH-dependent rate of swelling,dissolution or erosion (i.e., time-controlled release), polymers thatare degraded by enzymes (i.e., enzyme-controlled release) and polymersthat form firm layers that are destroyed by an increase in pressure(i.e., pressure-controlled release).

[0175] In still another embodiment, osmotic delivery systems are usedfor oral sustained release administration (Verma et al., Drug Dev. Ind.Pharm., 2000, 26:695-708). In a preferred embodiment, OROS® osmoticdelivery systems sold by Alza Corporation of Mountain View, Calif. areused for oral sustained release delivery devices (See for example,Theeuwes et al., U.S. Pat. No. 3,845,770; and Theeuwes et al, U.S. Pat.No. 3,916,899).

[0176] In yet another embodiment, a controlled-release system can beplaced in proximity of the target of the compounds and/or composition ofthe invention, thus requiring only a fraction of the systemic dose (See,e.g., Goodson, in “Medical Applications of Controlled Release,” supra,vol. 2, pp. 115-138 (1984)). Other controlled-release systems discussedin Langer, 1990, Science 249:1527-1533 may also be used.

[0177] The compounds, and/or compositions containing compound(s) ofstructural Formulae (IV), (V), (VI) or (VII) preferably provide GABAanalogs (e.g., gabapentin and pregablin) upon in vivo administration toa patient. While not wishing to bound by theory, the promoiety orpromoieties of the compounds and/or compositions of the invention may becleaved either chemically and/or enzymatically. One or more enzymespresent in the stomach, intestinal lumen, intestinal tissue, blood,liver, brain or any other suitable tissue of a mammal may enzymaticallycleave the promoiety or promoieties of the compounds and/or compositionsof the invention. The mechanism of cleavage is not important to thecurrent invention. Preferably, GABA analogs formed by cleavage ofprodrugs from the compounds of the invention do not contain substantialquantities of lactam contaminant (preferably, less than 0.5% by weight,more preferably, less than 0.2% by weight, most preferably less than0.1% by weight). The extent of release of lactam contaminant from theprodrugs of this invention may be assessed using the standard in vitroanalytical methods.

[0178] While not wishing to bound by theory, the promoiety orpromoieties of the compounds of structural Formulae (IV), (V), (VI) or(VII) may be cleaved prior to absorption by the gastrointestinal tract(e.g., within the stomach or intestinal lumen) and/or after absorptionby the gastrointestinal tract (e.g., in intestinal tissue, blood, liveror other suitable tissue of a mammal). If the promoiety or promoietiesof the compounds and/or compositions of the invention are cleaved priorto absorption by the gastrointestinal tract, the resulting GABA analogsmay be absorbed into the systemic circulation conventionally (e.g., viathe large neutral amino acid transporter located in the smallintestine). If the promoiety or promoieties of the compounds of theinvention are cleaved after absorption by the gastrointestinal tract,these GABA analog prodrugs may have the opportunity to be absorbed intothe systemic circulation either by passive diffusion, active transportor by both passive and active processes.

[0179] If the promoiety or promoieties of the compounds of structuralFormulae (IV), (V), (VI) or (VII) are cleaved after absorption by thegastrointestinal tract, these GABA analog prodrugs may have theopportunity to be absorbed into the systemic circulation from the largeintestine. In this situation, the compounds and/or compositions of theinvention are preferably administered as sustained release systems. In apreferred embodiment, the compounds and/or compositions of the inventionare delivered by oral sustained release administration. Preferably, inthis embodiment, the compounds and/or compositions of the invention areadministered twice per day (more preferably, once per day).

4.7 Compositions of the Invention

[0180] The present compositions contain a therapeutically effectiveamount of one or more compounds of the invention, preferably in purifiedform, together with a suitable amount of a pharmaceutically acceptablevehicle, which so as to provide the form for proper administration to apatient. When administered to a patient, the compounds of the inventionand pharmaceutically acceptable vehicles are preferably sterile. Wateris a preferred vehicle when the compound of the invention isadministered intravenously. Saline solutions and aqueous dextrose andglycerol solutions can also be employed as liquid vehicles, particularlyfor injectable solutions. Suitable pharmaceutical vehicles also includeexcipients such as starch, glucose, lactose, sucrose, gelatin, malt,rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate,talc, sodium chloride, dried skim milk, glycerol, propylene, glycol,water, ethanol and the like. The present compositions, if desired, canalso contain minor amounts of wetting or emulsifying agents, or pHbuffering agents. In addition, auxiliary, stabilizing, thickening,lubricating and coloring agents may be used.

[0181] In one embodiment, the compositions of the invention containingcompound(s) of structural Formulae (IV), (V), (VI) or (VII) are free oflactam side products formed by intramolecular cyclization. In apreferred embodiment, the compositions of the invention are stable toextended storage (preferably, greater than one year) without substantiallactam formation (preferably, less than 0.5% lactam by weight, morepreferably, less than 0.2% lactam by weight, most preferably, less than0.1% lactam by weight).

[0182] Pharmaceutical compositions comprising a compound of theinvention may be manufactured by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes. Pharmaceuticalcompositions may be formulated in conventional manner using one or morephysiologically acceptable carriers, diluents, excipients orauxiliaries, which facilitate processing of compounds of the inventioninto preparations which can be used pharmaceutically. Proper formulationis dependent upon the route of administration chosen.

[0183] The present compositions can take the form of solutions,suspensions, emulsion, tablets, pills, pellets, capsules, capsulescontaining liquids, powders, sustained-release formulations,suppositories, emulsions, aerosols, sprays, suspensions, or any otherform suitable for use. In one embodiment, the pharmaceuticallyacceptable vehicle is a capsule (see e.g., Grosswald et al., U.S. Pat.No. 5,698,155). Other examples of suitable pharmaceutical vehicles havebeen described in the art (see Remington's Pharmaceutical Sciences,Philadelphia College of Pharmacy and Science, 17th Edition, 1985).Preferred compositions of the invention are formulated for oraldelivery, particularly for oral sustained release administration.

[0184] Compositions for oral delivery may be in the form of tablets,lozenges, aqueous or oily suspensions, granules, powders, emulsions,capsules, syrups, or elixirs, for example. Orally administeredcompositions may contain one or more optionally agents, for example,sweetening agents such as fructose, aspartame or saccharin; flavoringagents such as peppermint, oil of wintergreen, or cherry coloring agentsand preserving agents, to provide a pharmaceutically palatablepreparation. Moreover, where in tablet or pill form, the compositionsmay be coated to delay disintegration and absorption in thegastrointestinal tract, thereby providing a sustained action over anextended period of time. Selectively permeable membranes surrounding anosmotically active driving compound are also suitable for orallyadministered compounds of the invention. In these later platforms, fluidfrom the environment surrounding the capsule is imbibed by the drivingcompound, which swells to displace the agent or agent compositionthrough an aperture. These delivery platforms can provide an essentiallyzero order delivery profile as opposed to the spiked profiles ofimmediate release formulations. A time delay material such as glycerolmonostearate or glycerol stearate may also be used. Oral compositionscan include standard vehicles such as mannitol, lactose, starch,magnesium stearate, sodium saccharine, cellulose, magnesium carbonate,etc. Such vehicles are preferably of pharmaceutical grade.

[0185] For oral liquid preparations such as, for example, suspensions,elixirs and solutions, suitable carriers, excipients or diluents includewater, saline, alkyleneglycols (e.g., propylene glycol), polyalkyleneglycols (e.g., polyethylene glycol) oils, alcohols, slightly acidicbuffers between pH 4 and pH 6 (e.g., acetate, citrate, ascorbate atbetween about 5 mM to about 50 mM) etc. Additionally, flavoring agents,preservatives, coloring agents, bile salts, acylcamitines and the likemay be added.

[0186] Compositions for administration via other routes may also becontemplated. For buccal administration, the compositions may take theform of tablets, lozenges, etc. formulated in conventional manner.Liquid drug formulations suitable for use with nebulizers and liquidspray devices and EHD aerosol devices will typically include a compoundof the invention with a pharmaceutically acceptable vehicle. Preferably,the pharmaceutically acceptable vehicle is a liquid such as alcohol,water, polyethylene glycol or a perfluorocarbon. Optionally, anothermaterial may be added to alter the aerosol properties of the solution orsuspension of compounds of the invention. Preferably, this material isliquid such as an alcohol, glycol, polyglycol or a fatty acid. Othermethods of formulating liquid drug solutions or suspension suitable foruse in aerosol devices are known to those of skill in the art (see,e.g., Biesalski, U.S. Pat. No. 5,112,598; Biesalski, U.S. Pat. No.5,556,611). A compound of the invention may also be formulated in rectalor vaginal compositions such as suppositories or retention enemas, e.g.,containing conventional suppository bases such as cocoa butter or otherglycerides. In addition to the formulations described previously, acompound of the invention may also be formulated as a depot preparation.Such long acting formulations may be administered by implantation (forexample, subcutaneously or intramuscularly) or by intramuscularinjection. Thus, for example, a compound of the invention may beformulated with suitable polymeric or hydrophobic materials (forexample, as an emulsion in an acceptable oil) or ion exchange resins, oras sparingly soluble derivatives, for example, as a sparingly solublesalt.

[0187] When a compound of the invention is acidic, it may be included inany of the above-described formulations as the free acid, apharmaceutically acceptable salt, a solvate or hydrate. Pharmaceuticallyacceptable salts substantially retain the activity of the free acid, maybe prepared by reaction with bases and tend to be more soluble inaqueous and other protic solvents than the corresponding free acid form.

4.8 Methods of Use and Doses

[0188] A compound of the invention, or compositions thereof, willgenerally be used in an amount effective to achieve the intendedpurpose. For use to treat or prevent diseases or disorders such asepilepsy, depression, anxiety, psychosis, faintness attacks,hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain(especially neuropathic pain and muscular and skeletal pain),inflammatory disease (i.e., arthritis), insomnia, gastrointestinaldisorders or ethanol withdrawal syndrome the compounds of Formulae (I),(V), (VI) or (VI), and compositions containing a compound of Formulae(IV), (V), (VI) or (VI), are administered or applied in atherapeutically effective amount.

[0189] The amount of a compound of the invention that will be effectivein the treatment of a particular disorder or condition disclosed hereinwill depend on the nature of the disorder or condition, and can bedetermined by standard clinical techniques known in the art aspreviously described. In addition, in vitro or in vivo assays mayoptionally be employed to help identify optimal dosage ranges. Theamount of a compound of the invention administered will, of course, bedependent on, among other factors, the subject being treated, the weightof the subject, the severity of the affliction, the manner ofadministration and the judgment of the prescribing physician.

[0190] For example, the dosage may be delivered in a pharmaceuticalcomposition by a single administration, by multiple applications orcontrolled release. In a preferred embodiment, the compounds of theinvention are delivered by oral sustained release administration.Preferably, in this embodiment, the compounds of the invention areadministered twice per day (more preferably, once per day). Dosing maybe repeated intermittently, may be provided alone or in combination withother drugs and may continue as long as required for effective treatmentof the disease state or disorder.

[0191] In the case of GABA analog prodrugs, suitable dosage ranges fororal administration are dependent on the potency of the parent GABAanalog drug, but are generally about 0.001 mg to about 200 mg of acompound of the invention per kilogram body weight. When the GABA analogis gabapentin, typical daily doses of the parent drug in adult patientsare 900 mg/day to 3600 mg/day and the dose of gabapentin prodrug may beadjusted to provide an equivalent molar quantity of gabapentin. OtherGABA analogs may be more potent than gabapentin (e.g., pregabalin), andlower doses may be appropriate for both the parent drug and any prodrug(measured on an equivalent molar basis). Dosage ranges may be readilydetermined by methods known to the skilled artisan.

[0192] The compounds of the invention are preferably assayed in vitroand in vivo, for the desired therapeutic or prophylactic activity, priorto use in humans. For example, in the case of a GABA analog used totreat convulsions, in vitro assays can be used to determine whetheradministration of a specific compound of Formulae (IV), (V), (VI) or(VI), or a combination thereof, is preferred for reducing convulsion.The compounds of the invention may also be demonstrated to be effectiveand safe using animal model systems.

[0193] Preferably, a therapeutically effective dose of a compound of theinvention described herein will provide therapeutic benefit withoutcausing substantial toxicity. Toxicity of compounds of the invention maybe determined using standard pharmaceutical procedures and may bereadily ascertained by the skilled artisan. The dose ratio between toxicand therapeutic effect is the therapeutic index. A compound of theinvention will preferably exhibit particularly high therapeutic indicesin treating disease and disorders. The dosage of a compound of theinventions described herein will preferably be within a range ofcirculating concentrations that include an effective dose with little orno toxicity.

4.9. Combination Therapy

[0194] In certain embodiments of the present invention, the compounds ofthe invention can be used in combination therapy with at least one othertherapeutic agent. The compound of the invention and the therapeuticagent can act additively or, more preferably, synergistically. In apreferred embodiment, a composition comprising a compound of theinvention is administered concurrently with the administration ofanother therapeutic agent, which can be part of the same composition asthe compound of the invention or a different composition. In anotherembodiment, a composition comprising a compound of the invention isadministered prior or subsequent to administration of anothertherapeutic agent.

5. EXAMPLES

[0195] The invention is further defined by reference to the followingexamples, which describe in detail, preparation of compounds of theinvention illustrate methods of synthesizing 1-(acyloxy)-alkylderivatives from 1-acyl-alkyl derivatives. It will be apparent to thoseskilled in the art that many modifications, both to materials andmethods, may be practiced without departing from the scope of theinvention.

[0196] In the examples below, the following abbreviations have thefollowing meanings. If an abbreviation is not defined, it has itsgenerally accepted meaning. Atm atmosphere Boc tert-butyloxycarbonyl Cbzcarbobenzyloxy DCC dicyclohexylcarbodiimide DMAP4-N,N-dimethylaminopyridine DMF N,N-dimethylformamide DMSOdimethylsulfoxide Fmoc 9-fluorenylmethyloxycarbonyl g gram h hour HPLChigh pressure liquid chromatography L liter LC/MS liquidchromatography/mass spectroscopy M molar m-CPBA meta-chloroperbenzoicacid min minute mL milliliter mmol millimoles NHS N-hydroxysuccinimidePBS phosphate buffered saline THF tetrahydrofuran TFA trifluoroaceticacid TLC thin layer chromatography TMS trimethylsilyl μL microliter μMmicromolar v/v volume to volume

5.1 Example 1:1-{[(α-Benzovloxybenzyloxy)carbonyl]aminomethyl}-1-Cyclohexane AceticAcid (1) Step A: 1,1-Cyclohexanediacetic anhydride (3)

[0197] A suspension of 1,1-cyclohexanediacetic acid (39.95 mmol) inacetic anhydride (159.8 mmol) was refluxed gently until a clear solutionwas obtained (ca. 1 h). The reaction mixture was kept at reflux foranother hour until the reaction was complete. The reaction mixture wascooled to room temperature and acetic acid and excess acetic anhydridewere removed under vacuum to afford 7.28 g (100%) of (3). ¹H NMR(CDCl₃): 2.65 (4H, s); 1.54-1.43 (10H, m).

Step B: 1-[(2-Cyanoethoxycarbonyl)methyl]-1-Cyclohexane Acetic Acid (5)

[0198] 8.2 mL of 1.6M butyllithium was added to a −78° C. solution of3-hydroxy-propionitrile (13.19 mmol) in 50 mL of THF. The reactionmixture was warmed to 30° C. and stirred for 30 minutes. Then, asolution of 1,1-cyclohexanediacetic anhydride (10.99 mmol) in 10 mL ofTHF was added dropwise. The reaction mixture was warmed to roomtemperature over a period of one hour and stirred at room temperaturewith monitoring by TLC. When the reaction was judged complete, thereaction mixture was quenched with saturated ammonium chloride solutionand THF was removed under reduced pressure. The aqueous layer wasextracted with ethyl acetate, washed with brine and dried over Na₂SO₄.After concentration in vacuo the residue was purified on silica gel (5%methanol in dichloromethane) to afford 2.64 g (95%) of the titlecompound. ¹H NMR (CDCl₃): δ 4.28 (2H, t, J=6.4 Hz); 2.71 (2H, t, J=6.4Hz); 2.61 (4H, m); 1.52-1.42 (10H, m).

Step C: 2-Cyanoethyl 1-isocyanatomethyl-1-Cyclohexane Acetate (7)

[0199] 1.5 mL of N-methyl morpholine (13.62 mmol) and 1.3 mL of ethylchloroformate (13.03 mmol) was added to a solution of1-[(2-cyanoethoxycarbonyl)-methyl]-1-cyclohexane acetic acid (5) (11.84mmol) in 30 mL of anhydrous THF at −20° C. under nitrogen atmosphere.The reaction mixture was stirred at −20° C. for 20 minutes, warmed to−5° C., an aqueous solution of NaN₃ (29.61 mmol, in 3.5 mL of H₂O) wasadded and then stirred for 30 minutes at −5° C. to −10° C. Then, THF wasremoved under reduced pressure and the residue was extracted with CH₂Cl₂and dried over Na₂SO₄. After concentration in vacuo the crude productwas dissolved in 20 mL of anhydrous toluene and refluxed for 20 minutes.The mixture was cooled to room temperature and toluene was removed underreduced pressure. The residue was purified on silica gel (15% ethylacetate in hexane) to afford 1.9 g (64%) of the title compound. ¹H NMR(CDCl₃): δ 4.29 (2H, t, J=6.0 Hz); 3.42 (2H, s); 2.73 (2H, t, J=6.0 Hz);2.44 (2H, s); 1.49-1.39 (10H, m).

Step D: 2-Cyanoethyl1-{[(α-Benzoylbenzyloxy)carbonyl]aminomethyl}-1-Cyclohexane Acetate (9)

[0200] A solution of benzoin (0.599 mmol) and 2-cyanoethyl1-isocyanatomethyl-1-cyclohexane acetate (7) (0.599 mmol) in 10 mL ofanhydrous toluene was refluxed overnight. The reaction mixture wasconcentrated and the residue purified on silica gel (40% ethyl acetatein hexane) to afford 230 mg (83%) of the title compound. ¹H NMR (CDCl₃):δ 7.95 (2H, dd, J=8.2, 1.4 Hz); 7.50-7.46 (3H, m); 7.41 (5H, m); 6.84(1H, s); 5.40 (1H, t, J=6.8 Hz); 4.26 (2H, m); 3.24 (2H, d, J=6.8 Hz);2.68 (2H, dt, J=2.4, 6.4 Hz); 2.36 (2H, d, J=1.2 Hz); 1.52-1.37 (10H,m).

Step E: 2-Cyanoethyl1-{[(α-Benzoyloxybenzyloxy)carbonyl]aminomethyl}-1-Cyclohexane Acetate(11)

[0201] A solution of 2-cyanoethyl1-{[(a-benzoylbenzyloxy)carbonyl]aminomethyl}-1-cyclohexane acetate (9)(115 mg, 0.248 mmol) in 4 mL of CH₂Cl₂ was added to a mixture of mCPBA(77%, 111 mg, 0.497 mmol) and Na₂CO₃ (52.7 mg, 0.497 mmol) at roomtemperature. The resulting suspension was stirred at room temperaturewith TLC monitoring. After completion of the reaction (about 8 hours)the reaction mixture was diluted with CH₂Cl₂, washed with saturatedNaHCO₃ solution and brine and dried over Na₂SO₄. After concentration invacuo the residue was purified on silica gel (40% ethyl acetate inhexane) to afford 89 mg (75%) of the title compound. ¹H NMR (CDCl₃): δ8.08 (2H, dd, J=6.8, 1.6 Hz); 7.91 (1H, s); 7.63-7.54 (3H, m); 7.44-7.40(5H, m); 5.42 (1H, t, J=6.4 Hz); 4.22 (2H, t, J=6.2 Hz); 3.25 (2H, dd,J=6.4, 4.6 Hz); 2.65 (2H, t, J=6.2 Hz); 2.35 (2H, s); 1.53-1.37 (10H,m). ¹³C NMR (CDCl₃): δ 172.11; 164.73; 154.75; 136.29; 133.70; 130.18;129.85; 129.63; 128.85; 128.68; 126.85; 117.11; 91.41; 58.94; 47.93;10.06; 38.09; 34.15; 26.00; 21.55; 18.16.

Step F: 1-{[(α-Benzoyloxybenzyloxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (1)

[0202] DBU (79.2 mg, 78 μL, 0.520 mmol) was added to a solution of2-cyanoethyl1-{[(α-benzoyloxybenzyloxy)carbonyl]aminomethyl}-1-cyclohexane acetate(11) (166 mg, 0.347 mmol) in 10 mL of CH₂Cl₂ at −10° C. The reactionmixture was stirred at O ° C. for 1 hour, then allowed to warm to roomtemperature, stirred for two hours and cooled to 0° C. Another 78 μL ofDBU was added, the reaction mixture was stirred for 3 hours at 0° C. andthen allowed to warm to room temperature. The reaction mixture wasdiluted with CH₂Cl₂, washed with citric acid and brine and dried overNa₂SO₄. The solvent was removed under reduced pressure and the residuewas purified by reversed phase HPLC to afford 7 mg (4.7%) of the titlecompound. M.p. 75.5-76.0° C. ¹H NMR (CDCl₃): δ 8.08 (2H, dd, J=8.8, 1.2Hz); 7.89 (1H, s); 7.63-7.55 (3H, m); 7.46-7.26 (5H, m); 5.38 (1H, t,J=6.8 Hz); 3.26 (2H, dd, J=6.8, 0.8 Hz); 2.34 (2H, s); 1.58-1.35 (10H,m). MS (ESI) m/z 424 (M−H⁻).

5.2 Example 2 Alternative Method for Preparation of1-{[(α-Benzovloxybenzyloxy)carbonyl]aminomethyl}-1-Cyclohexane AceticAcid (1) Step A: p-Nitrophenyl α-benzoylbenzylcarbonate (13)

[0203] A solution of benzoin (2.0 g, 9.42 mmol) in 60 mL of CH₂Cl₂ wastreated with DMAP (1.21 g, 9.89 mmol) and p-nitrophenyl-chloroformate(1.99 g, 9.89 mmol) at room temperature. The reaction mixture wasstirred for 3 hours at room temperature to afford the title compound,which was used in the next reaction without purification.

Step B: 1-{[(α-Benzoylbenzyloxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (15)

[0204] To a suspension of gabapentin (1.70 g, 9.90 mmol) in CH₂Cl₂ at 0°C. was added triethylamine (2.76 mL, 19.81 mmol) and TMSCl (2.51 mL,19.81 mmol). The reaction was then stirred for 30 min at roomtemperature. To this mixture was added compound (13) (prepared above) inCH₂Cl₂, and the resulting mixture was stirred at room temperature for 5hrs. The reaction mixture was diluted with dichloromethane, washed withbrine. The organic phase was dried over Na₂SO₄. The solvent was removedunder vacuum and the residue was purified by chromatography on silicagel with 5% methanol in CH₂Cl₂ to 3.78 g (90% over two steps) of thetitle compound. ¹H NMR (CDCl₃): δ 7.93 (2H, dd, J=7.2 Hz); 7.50-7.33(8H, m); 6.85 (1H, m); 5.58 (1H, t, J=6.8 Hz); 3.24 (2H, d, J=7.2 Hz);2.30 (2H, s); 1.48-1.35 (10H, m).

[0205] Step C:1-[{(α-Benzoyloxybenzyloxy)carbonyl]aminomethyl}-1-Cyclohexane AceticAcid (1)

[0206] mCPBA (77%, 2.07 g, 9.24 mmol) and NaHCO₃ (0.78 g, 9.24 mmol) wasadded to a solution of1-{[(cc-benzoylbenzyloxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid(15) (1.89 g, 4.62 mmol) in 40 mL of CH₂Cl₂ at room temperature and theresulting mixture was stirred at room temperature overnight. Thereaction mixture was acidified with citric acid, extracted with CH₂Cl₂and the organic phase was washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by reversephase preparative HPLC to afford 960 mg (49%) of the title compound.

5.3 Example 31-{[(α-Benzoyloxyethoxy)carbonyl]aminomethyl}-1-Cyclohexane Acetic Acid(17)

[0207] Following the procedure of Example 2, and substituting2-hydroxy-1-phenyl-1-propanone for benzoin, provided 5 mg of the titlecompound (17). ¹H NMR (CDCl₃, 400 MHz): δ 1.44-1.36 (m, 10H), 1.62 (d,J=5.6 Hz, 3H), 2.34 (s, 2H), 3.24 (d, J=6.8 Hz, 2H), 5.28 (t, J=6.8 Hz,1H), 7.06 (q. J=5.6 Hz, 1H), 7.44 (m, 2H), 7.56 (m, 1H), 8.03 (dd,J=8.4, 1.6 Hz, 2H).

5.4 Example 41-{[(α-Benzoyloxy-2-phenylethoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (19) Step A: 2-Phenyl-[1,3]-dithiane (21)

[0208] To a solution of benzaldehyde (10.6 g, 100 mmol) and 1,3-propanedithiol in CH₂Cl₂ (150 mL) at room temperature was dropwise addedBF₃.Et₂O (6.3 mL, 50 mmol) and the resulting mixture was stirred at roomtemperature for 2 hours. The reaction mixture was then diluted withCH₂Cl₂, filtered and the filtrate washed with brine, saturated NaHCO₃,brine and dried over Na₂SO₄. The solvent was removed under reducedpressure to afford a white solid, which was recrystallized from a 1:1mixture of ether and hexane to afford 17.0 g (87%) of the title compound(21) as white crystalline needles. ¹H NMR (CDCl₃, 400 MHz): δ 1.91 (m,1H), 2.14 (m, 1H), 2.89 (m, 2H), 3.04 (m, 2H), 5.16 (s, 1H), 7.35-7.28(m, 3H), 7.46 (m, 2H).

[0209] Step B: 2-Phenyl-1-(2-phenyl-[1,3]-dithian-2-yl)-ethanol (23)

[0210] To a solution of 2-phenyl-[1,3]-dithiane (21) (4.0 g, 20.4 mmol)in THF at −30° C. was added a 1.6 M solution of n-butyllithium in THF(15.3 mL, 24.4 mmol). After stirring for 30 minutes at −30° C., asolution of phenylacetylaldehyde (2.45 g, 20.4 mmol) in tetrahydrofuranwas added dropwise at −30° C. The resulting reaction mixture was stirredfor another hour at 0° C. The reaction was quenched with saturated NH₄Clsolution and extracted with ethyl acetate. The combined organic extractswere washed with saturated NH₄Cl solution, brine and dried over Na₂SO₄.After filtrating and concentrating, the crude product was purified byflash chromatography on silica gel, (25% ethyl acetate in hexanes), toafford 2.63 g (71%) of the title compound (23). ¹H NMR (CDCl₃, 400 MHz):δ 1.97 (m, 2H), 2.23 (dd, J=4.0, 1.2 Hz, 1H), 2.43 (dd, J=13.6, 10.2 Hz,1H), 2.77 (m, 4H), 3.02 (d, J=13.6 Hz, 1H), 4.07 (m, 1H), 7.44-7.13 (m,8H), 8.02 (dd, J=8.4, 1.4 Hz, 2H).

Step C: 2-Hydroxy-1,3-diphenyl-propan-1-one (25)

[0211] To a solution of 2-phenyl-1-(2-phenyl-[1,3]-dithian-2-yl)-ethanol(23) (2.50 g, 7.9 mmol) in 100 mL of a 9:1 mixture of acetonitrile andwater was added mercuric perchlorate hydrate (4.1 g, 10.3 mmol). Theresulting mixture was stirred at room temperature for 5 minutes and thinlayer chromatography indicated that the reaction was completed. Themixture was diluted with ethyl acetate, filtered through a pad of Celiteand the filtrate was washed with saturated NaHCO₃, brine and dried overNa₂SO₄. The solvent was removed under reduced pressure and the crudeproduct was purified by flash chromatography on silica gel, (20% ethylacetate in hexanes) to afford 1.32 g (74%) of the title compound (25).¹H NMR (CDCl₃, 400 MHz): δ 2.90 (dd, J=14.4, 7.0 Hz, 1H), 3.20 (dd,J=14.4, 4.0 Hz, 1H), 3.70 (d, J=6.8 Hz, 1H), 5.35 (m, 1H), 7.28-7.11 (m,5H), 7.53 (m, 2H), 7.65 (m, 1H), 7.93 (d, J=7.2 Hz, 2H).

Step D:1-{[(α-Benzoyloxy-2-phenylethoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (19)

[0212] Following the procedure of Example 2, and substituting2-hydroxy-1,3-diphenyl-propan-1-one for benzoin, provided 181 mg of thetitle compound (19). ¹H NMR (CDCl₃, 400 MHz): δ 1.45-1.29 (m, 10H), 2.24(d, J=13.6 Hz, 1H), 2.28 (d, J=13.6 Hz, 1H), 3.22 (m, 4H), 5.26 (t,J=6.6 Hz, 1H), 7.16 (t, J=5.6 Hz, 1H), 7.33-7.25 (m, 5H), 7.40 (m, 2H),7.57 (m, 1H), 8.02 (m, 2H).

5.5 Example 51-{[(α-(3-Methylbutanoyloxy)-2-phenylethoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (27)

[0213] Following the procedure of Example 4 and substituting3-methylbutyraldehyde for benzaldehyde in Step A, provided 95 mg of thetitle compound (27). ¹H NMR (CDCl₃, 400 MHz): δ 0.88-0.90 (m, 6H),1.16-1.29 (m, 10H), 2.06 (m, 1H), 2.16 (m, 2H), 2.26 (m, 2H), 3.08 (d,J=6.8 Hz, 2H), 3.19 (m, 2H), 5.22 (t, J=6.8 Hz, 1H), 6.93(t, J=6 Hz,1H), 7.31-7.23 (m, 5H).

5.6 Example 61-{[(α-Benzoyloxybutoxy)carbonyl]aminomethyl}-1-Cyclohexane Acetic Acid(29)

[0214] Following the procedure of Example 4 and substitutingbutyraldehyde for phenylacetaldehyde in Step B, provided 240 mg of thetitle compound (29). ¹H NMR (CDCl₃, 400 MHz): δ 0.99 (t, J=7.6 Hz, 3H),1.52-1.38 (m, 12H), 1.89 (m, 2H), 2.31 (s, 2H), 3.24 (m, 2H), 5.34 (t,J=6.6 Hz, 1H), 6.70 (t, J=5.6 Hz, 1H), 7.42 (m, 2H), 7.56 (m, 1H), 8.04(m, 2H).

5.7 Example 7 1-{[(α-Acetoxybutoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (31)

[0215] Following the procedure of Example 4, and substitutingacetaldehyde for benzaldehyde in Step A and substituting butyraldehydefor phenylacetaldehyde in Step B respectively, provided 42 mg of thetitle compound (31). ¹H NMR (CD₃OD, 400 MHz): δ 0.95 (m, 3H), 1.52-1.31(m, 12H), 1.72 (m, 2H), 2.02 (s, 3H), 2.27 (s, 2H), 3.20 (s, 2H), 6.67(t, J=5.6 Hz, 1H).

5.8 Example 81-{[(α-Butanoyloxybutoxy)carbonyl]aminomethyl}-1-Cyclohexane Acetic Acid(33)

[0216] Following the procedure of Example 2, and substituting butyroinfor benzoin, provided 210 mg of the title compound (33). ¹H NMR (CDCl₃,400 MHz); δ 0.93 (m, 6H), 1.37-1.76 (m, 16H), 2.30 (m, 4H), 3.23 (m,2H), 5.25 (broad triplet, 1H), 6.73 (m, 1H). MS (ESI) m/z 356.45 (M−H)⁺.

5.9 Example 91-{[(α-Acetoxybenzyloxy)carbonyl]aminomethyl}-1-Cyclohexane Acetic Acid(35)

[0217] Following the procedure of Example 2, and substitutingl-hydroxy-1-phenyl-propan-2-one for benzoin, provided the title compound(35). ¹H NMR (CDCl₃): δ 7.40 (5H, m); 5.95 (1H, s); 5.58 (1H, t, J=6.8Hz); 3.25 (2H, d, J=6.8 Hz); 2.34 (2H, s); 2.11 (3H, s); 1.50-1.38 (10H,m).

5.10 Example 101-{[(α-Isobutanoyloxybutoxy)carbonyl]aminomethyl}-1-Cyclohexane AceticAcid (37) Step A: 2-Isopropyl-1,3-Dithiane (39)

[0218] To a mixture of isobutyraldehyde (9.1 mL, 100 mmol) and1,3-propanedithiol (10 mL, 100 mmol) in dichloromethane at 0° C. wasadded boron trifluoride diethyl etherate (6.4 mL, 50 mmol). Theresulting mixture was stirred at 0° C. for 30 min and at roomtemperature for 30 min. The reaction mixture was washed with brine, 5%NaHCO₃, and brine again. The organic phase was separated and dried overNa₂SO₄, then concentrated to give 16 g (100%) of the title compound as ayellow liquid. This was carried to the next step without furtherpurification. ¹H NMR (CDCl₃, 400 MHz): δ 1.057 (d, J=7.2 Hz, 3H), 1.059(d, J=7.2 Hz, 3H), 1.80 (m, 1H), 1.97-2.08 (m, 2H), 2.82 (m, 4H), 4.00(d, J=5.2 Hz, 1H).

Step B: 2-Isopropyl-2-(a-Hydroxybutyl)-1,3-Dithiane (41)

[0219] To a solution of (39) (4 g, 24.7 mmol) in anhydroustetrahydrofuran (50 mL) at −20° C. was dropwise added n-butyl lithium(1.6M in hexane, 18.5 mL, 29.6 mmol). The stirred mixture was allowed towarm room temperature over 4 h and then cooled to −20° C. again. To thissolution was added slowly a solution of n-butyraldehyde (2.7 mL, 29.6mmol) in anhydrous tetrahydrofuran (10 mL). The resulting mixture wasstirred for 16 h between −20° C. and room temperature. The reaction wasquenched with saturated ammonium chloride solution and the mixtureextracted with ethyl acetate. The organic layer was separated and driedover Na₂SO₄. After removing the solvent under reduced pressure, flashcolumn chromatography of the residue on silica gel, eluting with 5%ethyl acetate/hexane provided 5 g (85%) of the title compound as ayellow oil. ¹H NMR (CDCl₃, 400 MHz): δ 0.96 (t, J=7.2 Hz, 3H), 1.11 (d,J=6.8, Hz, 3H), 1.17 (d, J=6.8 Hz, 3H), 1.42-1.52 (m, 2H), 1.76 (m, 1H),1.87-1.95 (m, 2H), 2.04 (m, 2H), 2.62 (m, 4H), 2.94 (m, 2H), 4.03 (d,J=5.2 Hz, 1H).

Step C: 4-Hydroxy-2-Methylheptan-3-one (43)

[0220] To a solution of (41) (5.0 g, 21.4 mmol) in acetonitrile (270 mL)was added under vigorous stirring a solution of Hg(ClO₄)₂ in methanol(30 mL). The resulting mixture was stirred at room temperature for 2 h.After filtration, the filtrate was carefully concentrated under reducedpressure without heating. Purification of the residue using silica gelflash column chromatography (10% ethyl acetate/hexane) provided 2.8 g(91%) of the title compound as colorless liquid. ¹H NMR (CDCl₃, 400MHz): δ 0.91 (t, J=7.2 Hz, 3H), 1.09 (d, J=7.2 Hz, 3H), 1.10 (d, J=7.2Hz, 3H), 1.35-1.46 (m, 4H), 1.75 (m, 1H), 2.80 (m, 1H), 3.45 (d, J=5.2Hz, 11H), 4.29 (m, 1H).

Step D: 2-Methylheptan-3-one-4-p-Nitrophenyl Carbonate (45)

[0221] To a mixture of (43) (1.1 g, 7.6 mmol), p-nitrophenylchloroformate (1.84 g, 9.2 mmol) in anhydrous dichloromethane at 0° C.was added slowly a solution of 4-dimethylaminopyridine (1.12 g, 9.2mmol) in dichloromethane. After stirring for 1 h at 0° C. and for 4 h atroom temperature, the reaction was quenched with 10% citric acid. Theorganic phase was separated, dried over Na₂SO₄, and concentrated invacuo. Flash column chromatography of the residue, eluting with 30%dichloromethane/hexane, provided 2 g (85%) of the title compound as anoff-white solid. ¹H NMR (CDCl₃, 400 MHz): δ 0.99 (t, J=7.6 Hz, 3H), 1.12(d, J=6.8 Hz, 3H), 1.18 (d, J=6.8 Hz, 3H), 1.51 (m, 2H), 1.84 (m, 2B),2.82 (m, 1H), 5.17 (m, 1H), 7.42 (d, J=6.8 Hz, 2H), 8.25 (d, J=6.8 Hz,2H).

[0222] Step E:1-{[(α-Isobutanoylbutoxy)carbonyl]aminomethyl}-1-Cyclohexane Acetic Acid(47)

[0223] To a mixture containing gabapentin (820 mg, 4.8 mmol) andtriethylamine (1.35 mL, 9.6 mmol) in dichloromethane (20 mL) was addedtrimethylchlorosilane (1.22 mL, 9.6 mmol) and the resulting mixture wasstirred for 20 min. To this solution was added (45) (1 g, 3.2 mmol) indichloromethane (10 mL) and the resulting mixture was stirred for 60min. The reaction mixture was washed with 10% citric acid (20 mL) andthe organic layer separated. The aqueous layer was further extractedwith ether (3×10 mL) and the combined organic extracts were dried overMgSO₄ then concentrated in vacuo. Chromatography of the residue onsilica gel, eluting with hexane:ethyl acetate (4:1) to removep-nitrophenol, then further eluting with hexane:ethyl acetate (1:4) gave780 mg (72%) of the title compound. ¹H NMR (CDCl₃, 400 MHz): δ 0.91 (t,J=7.2 Hz, 3H), 1.04 (d, J=6.8 Hz, 3H), 1.12 (d, J=6.8 Hz, 3H), 1.36-1.53(m, 12H), 1.74 (m, 2H), 2.33 (s, 2H), 2.78 (m, 1H), 3.22 (m, 2H), 5.11(m, 11H), 5.48 (t, 1H, NH). MS (ESI) m/z 342.24 (M+H⁺).

[0224] Step F:1-{[(α-Isobutanoyloxybutoxy)carbonyl]aminomethyl}-1-Cyclohexane AceticAcid (37)

[0225] To a solution of (47) (780 mg, 2.3 mmol) in dichloromethane (20mL) was added m-chloroperoxybenzoic acid (1.03 g, 4.6 mmol) and NaHCO₃(386 mg, 4.6 mmol). After stirring for 16 h at room temperature, anotherbatch of m-chloroperoxybenzoic acid (791 mg, 4.6 mmol) and NaHCO₃ (386mg, 4.6 mmol) was added. The resulting mixture was stirred for another 8h and then treated with 10% citric acid. After filtration, the organiclayer was separated, dried over Na₂SO₄, and concentrated. The residuewas purified by reverse phase preparative HPLC to afford 79 mg (11%) ofthe title compound. ¹H NMR (CDCl₃, 400 MHz): δ 0.94 (t, J=7.2 Hz, 3H),1.153 (d, J=7.2 Hz, 3H), 1.150 (d, J=7.2 Hz, 3H), 1.32-1.58 (m, 12H),1.74 (m, 2H), 2.28 (s, 2H), 2.56 (m, 1H), 3.23 (m, 2H), 5.27 (t, J=6.8Hz, 1H, NH), 6.71 (t, J=5.6 Hz, 1H). MS (ESI) m/z 358.30 (M+H⁺).

5.11 Example 11 α-(Benzoyloxy)benzyl-N-2-Phenethyl Carbamate (49)

[0226] Step A: (2-Oxo-1,2-Diphenylethyl)-N-2-Phenethyl Carbamate (51)

[0227] A solution of benzoin (2.0 g, 9.42 mmol) and phenethylisocyanate(4.16 g, 28.27 mmol) in toluene (60 mL) was refluxed overnight. Afterremoving the solvent under reduced pressure, the residue was purified byflash chromatography on silica gel (30% ethyl acetate in hexane) toafford 3.0 g (89%) the title compound. ¹H NMR (CDCl₃): δ 7.95 (2H, dd,J=8.4, 1.2 Hz); 7.50-7.17 (8H, m); 6.86 (1H, s); 5.08 (1H, t, J=7.2 Hz);3.45 (2H, q. J=7.2 Hz); 2.81 (2H, t, J=7.2 Hz).

Step B: α-(Benzoyloxy)benzyl-N-2-Phenethyl Carbamate (49)

[0228] Na₂CO₃ (165 mg, 1.56 mmol) and mCPBA (349 mg, 1.56 mmol) wasadded to a stirred, 0° C. solution of (51) (280 mg (0.78 mmol) indichloromethane (10 mL). The reaction mixture was allowed to warm toroom temperature and stirred for 24 hours. The reaction mixture was thendiluted with CH₂Cl₂, washed with 10% aqueous Na₂CO₃ solution, brine anddried over Na₂SO₄. The solvent was removed in vacuo and the residue waspurified by flash chromatography on silica gel (20% ethyl acetate inhexane) to afford 165 mg (45%) of the title compound. ¹H NMR (CDCl₃): δ8.10 (2H, dd, J=8.4, 1.2 Hz); 7.94 (1H, s); 7.60-7.17 (8H, m); 4.89 (1H,br s); 3.49 (2H, t, J=7.2 Hz); 2.84 (2H, t, J=7.2 Hz).

5.12 Example 12: 1-(Acetoxy)ethyl-N-2-Phenethyl Carbamate (53) Step A:(1-Methyl-2-Oxo-Propyl) N-2-Phenethyl Carbamate (55)

[0229] A solution of 3-hydroxy-2-butanone (440 mg, 5 mmol) andphenethylisocyanate (810 mg, 5.5 mmol) in toluene was stirred for twodays at 50° C. and the solvent was then removed under reduced pressure.The residue was purified by flash chromatography on silica gel (25%ethyl acetate in hexane) to afford 305 mg (26%) of the title compound.¹H NMR (CDCl₃): δ 7.31-7.19 (5H, m); 5.02 (1H, q, J=6.4 Hz); 4.89 (1H,br s); 3.47 (2H, t, J=6.4 Hz); 2.83 (2H, t, J=6.4 Hz); 2.15 (3H, s);1.35 (3H, d, J=6.4 Hz).

Step B: 1-(Acetoxy)ethyl-N-2-Phenethyl Carbamate (53)

[0230] mCPBA (77%, 580 mg, 2.60 mmol) was added to a stirred suspensionof (55) (305 mg, 1.29 mmol)) and Na₂CO₃ (137.6 mg, 1.29 mmol) indichloromethane (15 mL). The reaction mixture was stirred at roomtemperature for 48 hours, diluted with dichloromethane, washed with 10%Na₂CO₃ and brine and dried over Na₂SO₄. Solvent was removed underreduced pressure and the residue was purified by flash chromatography onsilica gel (20% ethyl acetate in hexanes) to afford 202 mg (62%) of thetitle compound. ¹H NMR (CDCl₃): δ 7.34-7.20 (5H, m); 6.82 (1H, q, J=5.2Hz); 4.80 (1H, br s); 3.44 (2H, t, J=6.8 Hz); 2.82 (2H, t, J=6.8 Hz);2.05 (3H, s); 1.44 (3H, d, J=5.2 Hz).

5.13 Example 13: 1-Acetoxy-1-Methylethyl-2-N-Phenethyl Carbamate (57)Step A: (1,1-Dimethyl-2-Oxo-Propyl) 2-N-Phenethyl Carbamate (59)

[0231] A solution of 3-hydroxy-3-methyl-2-butanone (510 mg, 5 mmol) andphenethylisocyanate (809 mg, 5.5 mmol) in toluene was stirred for threedays at 50° C. and then concentrated in vacuo. The residue was purifiedby flash chromatography on silica gel (25% ethyl acetate in hexanes) togive 218 mg (17.5%) of the title compound. ¹H NMR (CDCl₃): δ 7.33-7.20(5H, m); 4.85 (1H, br s, 1H); 3.44 (2H, t, J=6.8 Hz); 2.82 (2H, t, J=6.8Hz); 2.12 (3H, s); 1.43 (6H, s).

Step B: 1-Acetoxy-1-Methylethyl-2-N-Phenethyl Carbamate (57)

[0232] mCPBA (77%, 245 mg, 1.09 mmol) was added to a stirred suspensionof (59) (109 mg, 0.44 mmol) and Na₂CO₃ (46 mg, 0.44 mmol) indichloromethane (15 mL). The reaction mixture was stirred for 48 hoursat room temperature and another batch of mCPBA (247 mg, 1.09 mmol) wasadded. After stirring for 3 more days, the reaction mixture was dilutedwith dichloromethane, washed with 10% Na₂CO₃ and brine and dried overNa₂SO₄. After concentration in vacuo, the residue was purified by flashchromatography on silica gel (20% ethyl acetate in hexanes) to afford 50mg (43%) of (57). ¹H NMR (CDCl₃): δ 7.34-7.19 (5H, m); 4.86 (1H, br. s,1H); 3.43 (2H, t, J=6.7 Hz); 2.83 (2H, t, J=6.7 Hz). 2.09 (3H, s); 1.44(6H, s).

5.14 Example 14 Benzaldehyde Dibenzoylacetal (61)

[0233] 32% peracetic acid (0.67 mL, 3.79 mmol) was added to a suspensionof desyl benzoate (300 mg, 0.95 mmol) and Na₂CO₃ (402 mg, 3.79 mmol) indichloromethane (5 mL) at 0° C. The reaction mixture was stirredovernight at room temperature, diluted with dichloromethane, washed withsaturated NaHCO₃ and brine and dried over Na₂SO₄. Concentration in vacuoprovided 250 mg the title compound (79%). ¹H NMR (CDCl₃): δ 8.22 (1H,s); 7.73-7.71 (2H, m); 7.59-7.55 (2H, m); 7.48-7.42 (7H, m).

5.15 Example 15 Ethyl α-Benzoyloxybenzyl Methylphosphonate (63) Step A:Ethyl α-Benzoylbenzyl Methylphosphonate (65)

[0234] A solution of ethyl methyl phosphonate (1.81 mmol),diisopropylethylamine (2.71 mmol) and desyl bromide (1.81 mmol) in DMFwas stirred overnight at 70° C. The reaction mixture was cooled to roomtemperature, diluted with ether, washed with water, citric acid andbrine and the organic phase was dried over Na₂SO₄. After concentrationin vacuo, the crude product was purified by flash chromatography (2%methanol in dichloromethane) to afford 650 mg (54.2%) of ethyla-benzoylbenzyl methyl phosphonate (65) as four diasteroisomers. ¹H NMR(CDCl₃): δ 7.95-7.90 (2H, m); 7.51-7.35 (8H, m); 6.74 (1H, m); 4.19-3.70(2H, m); 1.64 (1.5H, d, J=18.0); 1.34 (1.5H, d, J=18 Hz); 1.25 (1.5H, t,J=7.2 Hz); 1.17 (1.5H, t, J=7.2 Hz).

Step B: Ethyl α-Benzoyloxybenzyl Methylphosphonate (63)

[0235] A suspension of ethyl α-benzoylbenzyl methyl phosphonate (275 mg,0.87 mmol) (65), mCPBA (77%, 388 mg, 1.73 mmol) and Na₂CO₃ (183 mg, 1.73mmol) in 5 mL of dichloromethane was stirred overnight at roomtemperature, diluted with dichloromethane, washed with saturated NaHCO₃and brine and dried over Na₂SO₄. Concentration in vacuo followed bypurification of the residue by flash chromatography on silica gel,eluting with 15% ethyl acetate in hexane, afforded 200 mg (69%) of ethylα-benzoyloxybenzyl methyl phosphonate (37). ¹H NMR (CDCl₃): 8.11-8.09(2H, m); 7.68-7.42 (9H, m); 4.22-3.70 (2H, m); 1.62 (1.5H, d, J=18.4Hz); 1.49 (1.5H, d, J=18.0); 1.25 (1.5H, t, J=7.2 Hz); 1.17 (1.5H, t,J=7.2 Hz).

5.16 Example 161-{[(α-(S)-Isobutanoyloxyisobutoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (181) and1-1[{(α-(R)-Isobutanoyloxyisobutoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (183) Step A: (S)- and(R)-N-(2-Hydroxy-3-Methylbutyroyl)morpholine (161) and (163)

[0236] To a stirred solution of (R)— or (S)-2-hydroxy-3-methylbutyricacid (0.1 mol) and N-hydroxysucciniimide (0.12 mol) in dichloromethane(200 mL) at ice-bath temperature under nitrogen atmosphere was addeddropwise a solution of dicyclohexylcarbodiimide (0.12 mol) indichloromethane (100 mL). After stirring at room temperature for 3 h,the reaction mixture was filtered and the precipitate was washed withdichloromethane (2×25 mL). The combined filtrate was cooled in anice-bath and then was added dropwise a solution of morpholine (0.22 mol)in dichloromethane (50 mL). The resulting mixture was stirred atice-bath temperature for 1 h and then overnight at room temperature. Thereaction mixture was filtered, and the precipitate was washed withdichloromethane (2×25 mL). The combined filtrate was washed successivelywith water (100 mL), 2% HCl solution (100 mL), brine (100 mL) and driedover anhydrous sodium sulfate. After removing the solvent under reducedpressure, the residue was purified by passing through a short silica gelcolumn using ethyl acetate as eluent to afford the title compounds in84-97% yield as viscous liquids. ¹H NMR (CDCl₃, 400 MHz): δ 0.80 (3H,d), 1.05 (3H, d), 1.76-1.84 (1H, m), 3.41 (2H, br. t), 3.54 (1H, br. s,OH), 3.62-3.71 (6H, m), 4.21 (1H, br. s). MS (ESI) m/z 188.26 (M+H⁺).

Step B: (S)- and (R)-N-(2-Benzyloxy-3-Methylbutyroyl)morpholine (165)and (167)

[0237] To a stirred suspension of sodium hydride (0.09 mol) in anhydrousdimethylformamide (25 mL) under nitrogen atmosphere at 0° C. was addeddropwise a solution of the appropriate α-hydroxyacid amide 161 or 163(0.75 mol) in dimethylformamide (5 mL). After stirring for 30 min, asolution of benzyl bromide (0.10 mol) in dimethylformamide (25 mL) wasadded dropwise into the reaction mixture at 0° C. The resulting mixturewas stirred at 0° C. for 1 h and then, at room temperature for 5-8 h(monitored by TLC). The mixture was poured onto crushed ice andacidified (to pH ˜6) with 5% HCl solution. The mixture was extractedwith dichloromethane (4×50 mL). The combined extract was washed withwater (2×50 mL), dried over anhydrous sodium sulfate and then,evaporated under reduced pressure. The residue was purified through ashort silica gel column eluting with 50-100% ethyl acetate and hexane toafford the title compounds in 85-90% yield as colorless viscous liquids.¹H NMR (CDCl₃, 400 MHz): δ 0.93 (3H, d), 1.06 (3H, d), 1.95-2.02 (1H,m), 3.56 (2H, br. t), 3.64-3.67 (6H, m), 3.78 (1H, d), 4.45 (1H, d),4.63 (1H, d), 7.31 (5H, m). MS (ESI) m/z 278.29 (M+H⁺).

[0238] Step C: (S)- and (R)-2,5-Dimethyl-4-Benzyloxy-Hexan-3-one (169)and (171)

[0239] To a stirred solution of compound 165 or 167 (0.05 mol) inanhydrous tetrahydrofuran (150 mL) under nitrogen atmosphere at −78° C.was added dropwise a solution of isopropyl lithium (0.075 mol). Afterstirring at −78° C. for 1-3 h (monitored by TLC), the reaction mixturewas poured into ice-cold saturated ammonium chloride solution (100 mL).The mixture was extracted with ethyl acetate (4×50 mL), washed withbrine (50 mL), dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by passing through ashort silica gel column using a gradient of 0-25% ethyl acetate/hexaneas eluent to afford the title compounds in 79-95 yield as colorlessviscous liquids. ¹H NMR (CDCl₃, 400 MHz): δ 0.95 (6H, br. d), 1.05 (3H,br. d), 1.07 (3H, br. d), 2.03-2.11 (1H, m), 2.92-2.99 (1H, m), 3.66(1H, br. d), 4.33 (1H, br. d), 4.62 (1H, br. d), 7.34 (3H, m), 7.35 (2H,m). MS (ESI) m/z 235.16 (M+H).

[0240] Step D: (S)- and (R)-2,5-Dimethyl-4-Hydroxy-Hexan-3-one (173) and(175)

[0241] To a solution of compound 169 or 171 (0.03 mol) in 20 mL ofmethanol was added 10% Pd-C (50% w/w) under nitrogen atmosphere. Theresulting mixture was agitated with a stream of hydrogen (50 psi) atroom temperature for 24 hrs (monitored by TLC). The reaction mixture wasfiltered through a Celite® pad, and the precipitate washed with methanol(3×25 mL). The combined filtrate was concentrated under reduced pressureat cold water bath temperature (<20° C.). The residue was passed througha short silica gel column using a gradient of 0-25% diethylether andn-pentane as eluents to afford the title compounds in 89-98% yield ascolorless liquids. The enantiomeric excess of these chiralhydroxyketones was determined from the ¹H NMR spectral data of theirMosher ester derivatives (prepared as in Step E below). ¹H NMR (CDCl₃,400 MHz): δ 0.69 (3H, br. d), 1.10 (3H, br. d), 1.11 (3H, br. d), 1.13(3H, br. d), 2.12-2.19 (1H, m), 2.81 (1H, br. hept), 3.37 (1H, br. d,OH), 4.29 (1H, br. d). MS (ESI) m/z 145.12 (M+H⁺).

Step E: Synthesis of Mosher Esters of (173) and (175)

[0242] To a stirred solution containing the appropriate a-hydroxyketone(0.1 mmol), triethylamine (0.12 mmol) and DMAP (0.04 mmol) in anhydrousdichloromethane under nitrogen atmosphere at 0° C. was added a solutionof (S)-(+)-Mosher acid chloride (0.12 mmol) in dichloromethane (1 mL).The resulting mixture was stirred at 0° C. for 2 h and then, at roomtemperature for 4-6 h (monitored by TLC). The reaction mixture waspoured into ice-cold water (15 mL) and extracted with dichloromethane(3×15 mL). The combined extract was washed successively with 10% aqueousNaHCO₃ solution (15 mL) and brine (15 mL). The organic layer wasseparated, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was quickly passed through a short silicagel column using 50% diethyl ether and hexane as eluents to remove theDMAP and the organic salts thereof as polar impurities in the crudereaction mixture. The diastereomeric excess of the Mosher esters wasdetermined from the ¹H NMR spectral data to be >90% for each isomer.

Mosher ester of (173)

[0243] Colorless viscous liquid (de=>90%). ¹H NMR (CDCl₃, 400 MHz): δ0.85 (3H, d), 1.06 (3H, d), 1.10 (3H, d), 1.19 (3H, d), 2.32-2.39 (1H,m), 2.77 (1H, hpt.), 3.57 (3H, s), 5.23 (1H, d), 7.42 (3H, m), 7.59 (2H,m).

Mosher Ester of (175)

[0244] Colorless viscous liquid ((de=>90%). ¹H NMR (CDCl₃, 400 MHz): δ0.83 (3H, d), 0.96 (3H, d), 1.09 (3H, d), 1.22 (3H, d), 2.26-2.34 (1H,m), 2.79 (1H, hpt.), 3.62 (3H, s), 5.21 (1H, d), 7.42 (3H, m), 7.71 (2H,m).

Step F:1-{[α-(S)-Isobutanoylisobutoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (177) and1-{[(α-(R)-Isobutanoylisobutoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (179)

[0245] To a stirred solution of α-hydroxyketone 173 or 175 (1 g, 7 mmol)and DMAP (1 g, 9 mmol) in anhydrous dichloromethane (25 mL) undernitrogen atmosphere at 0° C. was added dropwise a solution ofp-nitrophenylchloroformate in dichloromethane (25 mL). The resultingmixture was stirred for 5-6 h (monitored by TLC) and then poured into10% aqueous NaHCO₃ solution and extracted with dichloromethane (2×25mL). The combined extract was washed with brine (25 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure toafford the corresponding carbonate derivative in nearly quantitativeyield.

[0246] In a separate flask, gabapentin (1.71 g, 10 mmol) was treatedwith chlorotrimethylsilane (3.16 g, 21 mmol) in dichloromethane (100 mL)in the presence triethylamine (2.22 g, 22 mmol) at 0° C. for 30 min. Tothis reaction mixture, a solution of the appropriate carbonate describedabove in dichloromethane (25 mL) was added at 0° C. followed by pyridine(0.79 g, 10 mmol). The resulting mixture was stirred at 0° C. for 3 hand then at room temperature for 12-15 h (monitored by LC/MS). Thereaction mixture was poured into cold water and extracted withdichloromethane (3×50 mL). The combined extract was washed successivelywith 2% aqueous HCl solution (50 mL), brine (2×50 mL) and dried overanhydrous sodium sulfate. After evaporating the solvent under reducedpressure the residue was purified by preparative LC/MS to afford thetitle compounds in 35-48% yield as colorless viscous liquids. ¹H NMR(CDCl₃, 400 MHz): δ 0.86 (3H, d), 1.04 (6H, m), 1.13 (3H, d), 1.35-1.54(10H, m), 2.21-2.26 (1H, m), 2.33 (2H, d), 2.78 (1H, hpt.), 3.22 (2H,br. t), 5.04 (1H, d), 5.43 (1H, br. t, NH). MS (ESI) m/z 342.42 (M+H⁺).

Step G:1-{[(α-(S)-Isobutanoyloxyisobutoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (181) and1-{[(α-(R)-Isobutanoyloxyisobutoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (183)

[0247] To a stirred suspension of m-chloroperoxybenzoic acid (1.55 g, 9mmol) and sodium hydrogen-phosphate (1.71 g, 9 mmol) in dichloromethane(50 mL) at room temperature was added a solution of compound 177 or 179(1 g, 3 mmol) in dichloromethane (50 mL). The resulting mixture wasstirred at room temperature for 48 h (monitored by LC/MS) and thenpoured into cold water (100 mL) and acidified (to pH ˜5) with 5% aqueousHCl solution. The mixture was extracted with ethyl acetate (4×50 mL).The combined organic extract was washed with brine (50 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by preparative LC/MS technique to afford the titlecompounds as colorless viscous liquids in 4-10% yield. ¹H NMR (CDCl₃,400 MHz): δ 0.94 (6H, d), 1.14 (3H, d), 1.15 (3H, d), 1.38-1.50 (10H,m), 1.99 (1H, m), 2.30 (2H, s), 2.53 (1H, hpt), 3.22 (2H, br. t), 5.29(1H, br. t, NH), 6.11 (1H, br. s). ¹H NMR (CD₃OD, 400 MHz): 0.95 (d,J=7.2 Hz, 3H), 0.97 (d, J=7.2 Hz, 3H), 1.05 (d, 3H), 1.06 (d, 3H),1.32-1.58 (m, 10H), 1.98 (m, 1H), 2.24 (s, 2H), 2.45 (m, 1H), 3.24 (m,2H), 6.42 (d, 1H). MS (ESI) m/z 356.28 (M−H)⁻.

[0248] Finally, it should be noted that there are alternative ways ofimplementing the present invention. Accordingly, the present embodimentsare to be considered as illustrative and not restrictive, and theinvention is not to be limited to the details given herein, but may bemodified within the scope and equivalents of the appended claims.

[0249] All publications and patents cited herein are incorporated byreference in their entirety.

What is claimed is:
 1. A 1-acyl-alkyl derivative comprising a compoundof structural Formula (I):

or a pharmaceutically acceptable salt, hydrate or solvate thereof,wherein: n is 0 or 1; q is 0 or 1; provided that n and q are 0 unless Yis —NRR′ or —OR; Y is —NRR′, —OR, —C(O)R, —P(O)(OR′)R or —P(O)(OR′)(OR),wherein: —NRR′ is derived from a drug containing a primary or secondaryamino group, with the proviso that the drug is not norfloxacin,pamidronate or a 2-aminomethyl-3-methylthiazolo[3,2a]benzimidazolederivative; —OR is derived from a drug containing a hydroxyl group, withthe proviso that the drug is not 1-hydroxymethyl 5-fluorouracil or a1-aryl-6,7-dialkoxyisoquinolone phosphodiesterase inhibitor; —OC(O)R isderived from a drug containing a carboxylic acid or carboxylate group,with the proviso that the drug is not a 6-azauracil-5-carboxylic acidderivative; —OP(O)(OR′)R is derived from a drug containing a phosphonicacid or phosphonate group; —OP(O)(OR′)(OR) is derived from a drugcontaining a phosphoric acid or phosphate group, with the proviso thatthe drug is not cytarabine-5′-phosphate or a-tocopherol phosphate; R¹ ishydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl or a C₂₃ bileacid moiety or optionally, R¹ and either R² or R³, together with theatoms to which R¹ and R² or R³ are attached, form a cycloalkyl,substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkylring, which is optionally fused to an aryl, substituted aryl,heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring; R² and R³ areindependently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl,substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl,cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl,substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkylor optionally, R² and R³ together with the atom to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring; R²¹ is independently hydrogen, alkylor substituted alkyl; and R²² is independently hydrogen, alkyl,substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl,acylamino, substituted acylamino, alkylamino, substituted alkylamino,alklysulfinyl, substituted alkylsulfinyl, alkylsulfonyl, substitutedalkylsulfonyl, alkylthio, substituted alkylthio, alkoxycarbonyl,substituted alkylthio, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, aryloxy, substituted aryloxy, carbamoyl, substitutedcarbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino,halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heteroalkyloxy, substituted heteroalkyloxy, heteroaryloxy, substitutedheteroaryloxy or optionally, R²² together with the carbon atom to whichit is attached, the adjacent nitrogen atom and R²¹ substituent form acycloheteroalkyl or substituted cycloheteroalkyl ring.
 2. The compoundof claim 1, wherein q is
 0. 3. The compound of claim 1, wherein: q is 1;and R²² is hydrogen, alkanyl, substituted alkanyl, aryl, substitutedaryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl,heteroarylalkyl and substituted heteroarylalkanyl or optionally, R²²together with the carbon atom to which it is attached, the adjacentnitrogen atom and R²¹ substituent form a cycloheteroalkyl or substitutedcycloheteroalkyl ring.
 4. The compound of claim 3, wherein R²² isselected from the group consisting of hydrogen, methyl, 2-propyl,2-butyl, isobutyl, t-butyl, cyclopentyl or cyclohexyl, —CH₂OH,—CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃,CH₂SH, —CH₂(CH₂)₃NH₂ or —CH₂CH₂CH₂NHC(NH)NH₂, phenyl, benzyl,4-hydroxybenzyl, 2-imidazolyl and 2-indolyl, or optionally, R²¹ and R²²together with the atoms to which they are attached, form a pyrrolidinering.
 5. The compound of claim 1, wherein: R¹ is selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl, cycloalkyl, cycloheteroalkyl, heteroaryl, substitutedand heteroaryl; and R² and R³ are independently hydrogen, alkyl,alkoxycarbonyl, aryl, arylalkyl, carbamoyl, cycloalkoxycarbonyl orheteroaryl.
 6. The compound of claim 5, wherein: R¹ is selected from thegroup consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl,phenethyl, styryl or 3-pyridyl; and R² and R³ are independently selectedfrom the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, cyclohexyloxycarbonyl, phenyl,benzyl, phenethyl or 3-pyridyl.
 7. The compound of claim 6, wherein: R¹is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl; R² is selectedfrom the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, phenyl, benzyl, phenethyl or3-pyridyl, and R³ is hydrogen.
 8. The compound of claim 6, wherein: R¹is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl; R² is selectedfrom the group consisting of methyl, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl and cyclohexyloxycarbonyl, andR³ is methyl.
 9. The compound of claim 1, wherein: R¹ and R² togetherwith the atoms to which they are attached, form a cycloalkyl,substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkylring.
 10. The compound of claim 9, wherein: R¹ and R² together with theatoms to which they are attached, form a cyclobutyl, cyclopentyl orcyclohexyl ring.
 11. The compound of claim 1 or claim 7, wherein: Y is—NRR′; and —NRR′ is derived from a drug selected from the groupconsisting of amifostine, baclofen, carbidopa, clonidine, ciprofloxacin,cisapride, daunorubicin, doxorubicin, fenoterol, gabapentin, gentamycin,kanamycin, levodopa, meropenem, metazoline, neomycin, pregabalin,tobramycin, trovafloxacin and vigabatrin.
 12. The compound of claim 1 orclaim 7, wherein: Y is —OR; and —OR is derived from a drug selected fromthe group consisting of adenosine, cromolyn, cytarabine, decitabine,didanosine, docetaxel, gemcitabine, norgestrel, paclitaxel, pentostatinand vinblastine.
 13. The compound of claim 1 or claim 7, wherein: Y is—C(O)R; and —OC(O)R is derived from a drug selected from the groupconsisting of acametacin, argatroban, BCX-140, BCX-1812, cefotaxime,ceftazidime, ceftriaxone, cromolyn, foscarnet, lamifiban, melagatran,meropenem and zanamivir.
 14. The compound of claim 1 or claim 7,wherein: Y is —P(O)(OR′)R; and —OP(O)(OR′)R is derived from a drugselected from the group consisting of alendronate, cidofovir,clodronate, foscarnet, ibandronate, midafotel, olpadronate, pamidronate,residronate and zoledronate.
 15. The compound of claim 1 or claim 7,wherein: Y is —P(O)(OR′)(OR); and —OP(O)(OR′)(OR) is derived from a drugselected from the group consisting of bucladesine, choline alfoscerate,citocoline, fludarabine phosphate, fosopamine, GP-668, perfosine andtriciribine.
 16. A 1-acyl-alkyl derivative comprising a compound havinga structural formula selected from the group consisting of Formulae (IV)and (V):

or a pharmaceutically acceptable salt, hydrate or solvate thereof,wherein: q, R¹, R², R³, R²¹ and R²² are as defined in claim 1; X is O orS; and R²⁰ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl.
 17. The compound of claim 16, wherein R²⁰ is selectedfrom the group consisting of hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl,substituted cycloalkanyl, cycloheteroalkanyl and substitutedcycloheteroalkanyl.
 18. The compound of claim 16, wherein X is O and R²⁰is hydrogen.
 19. The compound of claim 16, wherein X is O and R²⁰ isalkanyl, substituted alkanyl, alkenyl, substituted alkenyl, aryl orsubstituted aryl.
 20. The compound of claim 19, wherein R²⁰ is—C(CH₃)═CH₂, —CH₂C(═O)N(CH₃)₂, 4-fluorophenyl or


21. The compound of claim 16, wherein q is
 0. 22. The compound of claim16, wherein q is 1, and R²² is selected from the group consisting ofhydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl,arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkyl andsubstituted heteroarylalkanyl, or optionally, R²² together with thecarbon atom to which it is attached, the adjacent nitrogen atom and R²¹substituent form a cycloheteroalkyl or substituted cycloheteroalkylring.
 23. The compound of claim 22, wherein R²² is selected from thegroup consisting of hydrogen, methyl, 2-propyl, 2-butyl, isobutyl,t-butyl, cyclopentyl or cyclohexyl, —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H,—CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, CH₂SH, —CH₂(CH₂)₃NH₂or —CH₂CH₂CH₂NHC(NH)NH₂, phenyl, benzyl, 4-hydroxybenzyl, 2-imidazolyland 2-indolyl, or optionally, R²¹ and R²² together with the atoms towhich they are attached, form a pyrrolidine ring.
 24. The compound ofclaim 16, wherein: R¹ is selected from the group consisting of hydrogen,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, cycloalkyl,cycloheteroalkyl, heteroaryl, substituted and heteroaryl; and R² and R³are independently hydrogen, alkyl, alkoxycarbonyl, aryl, arylalkyl,carbamoyl, cycloalkoxycarbonyl or heteroaryl.
 25. The compound of claim24, wherein: R¹ is selected from the group consisting of methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, sec-pentyl, neopentyl, cyclobutyl, cyclopentyl, cyclohexyl,phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl and 3-pyridyl; and R²and R³ are independently selected from the group consisting of hydrogen,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, cyclohexyloxycarbonyl, phenyl,benzyl, phenethyl and 3-pyridyl.
 26. The compound of claim 25, wherein:R² is selected from the group consisting of hydrogen, methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, phenyl,benzyl, phenethyl and 3-pyridyl, and R³ is hydrogen.
 27. The compound ofclaim 24, wherein: R¹ is selected from the group consisting of methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, sec-pentyl, neopentyl, cyclobutyl, cyclopentyl,cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl and3-pyridyl; R² is selected from the group consisting of methyl,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl,tert-butoxycarbonyl and cyclohexyloxycarbonyl, and R³ is methyl.
 28. Thecompound of claim 16, wherein: R¹ and R² together with the atoms towhich they are attached, form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring.
 29. The compoundof claim 28, wherein: R¹ and R² together with the atoms to which theyare attached, form a cyclobutyl, cyclopentyl or cyclohexyl ring.
 30. Amethod of synthesizing a 1-(acyloxy)-alkyl prodrug of structural Formula(II), the method comprising contacting a compound of structural Formula(I) with an oxidant:

wherein: n, q, Y, R¹, R², R³, R²¹ and R²² are as defined in claim
 1. 31.The method of claim 30, wherein the oxidation is performed in thepresence of a solvent.
 32. The method of claim 31, wherein the solventis selected from the group consisting of t-butanol, diethylether, aceticacid, hexane, dichloroethane, dichloromethane, ethyl acetate,acetonitrile, methanol, chloroform and water.
 33. The method of claim30, wherein the oxidant comprises a peroxyacid.
 34. The method of claim33, wherein the peroxyacid is selected from the group consisting ofCF₃CO₃H, MeCO₃H, mCPBA, monopermaleic acid, mono-o-perphthalic acid, 3,5dinitroperbenzoic acid, o-nitroperbenzoic acid, m-nitroperbenzoic acid,p-nitroperbenzoic acid, performic acid, perbenzoic acid, persulfuricacid, and salts thereof.
 35. The method of claim 30, wherein the oxidantcomprises a peroxide.
 36. The method of claim 35, wherein the peroxideis selected from the group consisting of H₂O₂, t-BuOOH and (TMS)₂O₂. 37.The method of claim 30, wherein the oxidant comprises an organismselected from the group consisting of yeast and bacteria.
 38. The methodof claim 37, wherein the organism comprises the yeast Saccharomycescerevisiae.
 39. The method of claim 37, wherein the organism comprisesthe bacterium Acinetobacter sp. NCIB
 9871. 40. The method of claim 30,wherein the oxidant comprises an enzyme.
 41. The method of claim 40,wherein the enzyme comprises cyclohexanone monooxygenase.
 42. The methodof claim 30, wherein the oxidation is performed in the presence of atransition metal complex.
 43. The method of claim 42, wherein thetransition metal complex is selected from the group consisting of:


44. The method of claim 30, wherein the molar ratio of oxidant to theFormula (I) compound is between 8:1 and 1:1.
 45. The method of claim 44,wherein the molar ratio of oxidant to the Formula (I) compound isapproximately 2:1.
 46. The method of claim 30, wherein the oxidation isperformed in the presence of a Lewis acid or protic acid.
 47. The methodof claim 46, wherein the Lewis acid is selected from the groupconsisting of BF₃, SeO₂, MeReO₃, MnO₂, SnCl₄, Sc(OTf)₃, Ti(O-iPr)₄,Al₂O₃ and Fe₂O₃.
 48. The method of claim 46, wherein the protic acid isselected from the group consisting of acetic acid, p-toluenesulfonicacid, methanesulfonic acid, trifluoroacetic acid,trifluoromethanesulfonic acid, hydrochloric acid and sulfuric acid. 49.The method of claim 30, wherein the oxidation is performed in thepresence of a base.
 50. The method of claim 49, wherein the base isselected from the group consisting of Na₂HPO₄, K₂HPO₄, NaHCO₃, Na₂CO₃and Li₂CO₃.
 51. The method of claim 30, wherein the oxidation isperformed at a temperature between about −25° C. and about 120° C. 52.The method of claim 30, wherein the oxidation is performed at atemperature between about −25° C. and about 0° C.
 53. The method ofclaim 30, wherein the carbon atom to which R² and R³ are attached is achiral center.
 54. The method of claim 53, wherein the Formula (II)compound is not a racemate.
 55. The method of claim 30 or claim 34,wherein: Y is —NRR′; and —NRR′ is derived from a drug selected from thegroup consisting of amifostine, baclofen, carbidopa, clonidine,ciprofloxacin, cisapride, daunorubicin, doxorubicin, fenoterol,gabapentin, gentamycin, kanamycin, levodopa, meropenem, metazoline,neomycin, pregabalin, tobramycin, trovafloxacin and vigabatrin.
 56. Themethod of claim 30 or claim 34, wherein: Y is —OR; and —OR is derivedfrom a drug selected from the group consisting of adenosine, cromolyn,cytarabine, decitabine, didanosine, docetaxel, gemcitabine, norgestrel,paclitaxel, pentostatin and vinblastine.
 57. The method of claim 30 orclaim 34, wherein: Y is —C(O)R; and —OC(O)R is derived from a drugselected from the group consisting of acametacin, argatroban, BCX-140,BCX-1812, cefotaxime, ceftazidime, ceftriaxone, cromolyn, foscarnet,lamifiban, melagatran, meropenem and zanamivir.
 58. The method of claim30 or claim 34, wherein: Y is —P(O)(OR′)R; and —OP(O)(OR′)R is derivedfrom a drug selected from the group consisting of alendronate,cidofovir, clodronate, foscarnet, ibandronate, midafotel, olpadronate,pamidronate, residronate and zoledronate.
 59. The method of claim 30 orclaim 34, wherein: Y is —P(O)(OR′)(OR); and —OP(O)(OR′)(OR) is derivedfrom a drug selected from the group consisting of bucladesine, cholinealfoscerate, citocoline, fludarabine phosphate, fosopamine, GP-668,perfosine and triciribine.
 60. A method of synthesizing a1-(acyloxy)-alkyl derivative of Formulae (VI) or (VII), the methodcomprising contacting a compound of Formulae (IV) or (V) with an oxidantto form a compound of Formulae (VI) or (VII), respectively:

wherein: q, X, R¹, R², R³, R²⁰, and R²² are as defined in claim 16; 61.The method of claim 60, wherein X is O and R²⁰ is hydrogen.
 62. Themethod of claim 60, wherein X is O and R²⁰ is alkanyl, substitutedalkanyl, alkenyl, substituted alkenyl, aryl or substituted aryl.
 63. Themethod of claim 61, wherein q is
 0. 64. The method of claim 62, whereinq is
 0. 65. The method of claim 60 wherein: R¹ is selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, heteroaryl,substituted and heteroaryl; and R² and R³ are independently hydrogen,alkyl, alkoxycarbonyl, aryl, arylalkyl, carbamoyl, cycloalkoxycarbonylor heteroaryl.
 66. The method of claim 65, wherein: R¹ is selected fromthe group consisting of methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl,neopentyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl,benzyl, phenethyl, styryl and 3-pyridyl; and R² and R³ are independentlyselected from the group consisting of hydrogen, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl,cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl and 3-pyridyl.
 67. Themethod of claim 66, wherein: R¹ is selected from the group consisting ofmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, cyclobutyl,cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl,styryl and 3-pyridyl; R² is selected from the group consisting ofhydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, phenyl, benzyl, phenethyl and 3-pyridyl, and R³ is hydrogen.68. The method of claim 66, wherein: R¹ is selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl,phenethyl, styryl and 3-pyridyl; R² is selected from the groupconsisting of methyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl and cyclohexyloxycarbonyl, andR³ is methyl.
 69. The method of claim 60, wherein R¹ and R² togetherwith the atoms to which they are attached, form a cycloalkyl,substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkylring.
 70. The method of claim 69, wherein R¹ and R² together with theatoms to which they are attached, form a cyclobutyl, cyclopentyl orcyclohexyl ring.
 71. The method of claim 60 or claim 67, wherein theoxidation is performed in the presence of a solvent.
 72. The method ofclaim 71, wherein the solvent is selected from the group consisting oft-butanol, diethylether, acetic acid, hexane, dichloroethane,dichloromethane, ethyl acetate, acetonitrile, methanol, chloroform andwater.
 73. The method of claim 60 or claim 67, wherein the oxidantcomprises a peroxyacid.
 74. The method of claim 73, wherein theperoxyacid is selected from the group consisting of CF₃CO₃H, MeCO₃H,mCPBA, monopermaleic acid, mono-o-perphthalic acid, 3,5dinitroperbenzoic acid, o-nitroperbenzoic acid, m-nitroperbenzoic acid,p-nitroperbenzoic acid, performic acid, perbenzoic acid, persulfuricacid, and salts thereof.
 75. The method of claim 60 or claim 67, whereinthe oxidant comprises a peroxide.
 76. The method of claim 75, whereinthe peroxide is selected from the group consisting of H₂O₂, t-BuOOH and(TMS)₂O₂.
 77. The method of claim 60 or claim 67, wherein the oxidantcomprises an organism selected from the group consisting of yeast andbacteria.
 78. The method of claim 77, wherein the oxidant comprises theyeast Saccharomyces cerevisiae.
 79. The method of claim 77, wherein theoxidant comprises the bacterium Acinetobacter sp. NCIB
 9871. 80. Themethod of claim 60 or claim 67, wherein the oxidant comprises an enzyme.81. The method of claim 80, wherein the enzyme comprises cyclohexanonemonooxygenase.
 82. The method of claim 60 or claim 67, wherein theoxidation is performed in the presence of a transition metal complex.83. The method of claim 82, wherein the transition metal complex isselected from the group consisting of:


84. The method of claim 60 or claim 67, wherein the molar ratio ofoxidant to the compound of Formulae (IV) or (V) is between 8:1 and 1:1.85. The method of claim 84, wherein the molar ratio of oxidant to thecompound of Formulae (IV) or (V) is approximately 2:1.
 86. The method ofclaim 60 or claim 67, wherein the oxidation is performed in the presenceof a Lewis acid or protic acid.
 87. The method of claim 86, wherein theLewis acid is selected from the group consisting of BF₃, SeO₂, MeReO₃,MnO₂, SnCl₄, Sc(OTf)₃, Ti(O-iPr)₄, Al₂O₃ and Fe₂O₃.
 88. The method ofclaim 86, wherein the protic acid is selected from the group consistingof acetic acid, p-toluenesulfonic acid, methanesulfonic acid,trifluoroacetic acid, trifluoromethanesulfonic acid, hydrochloric acidand sulfuric acid.
 89. The method of claim 60 or claim 67, wherein theoxidation is performed in the presence of a base.
 90. The method ofclaim 89, wherein the base is selected from the group consisting ofNa₂HPO₄, K₂HPO₄, NaHCO₃, Na₂CO₃ and Li₂CO₃.
 91. The method of claim 60or claim 67, wherein the oxidation is performed at a temperature betweenabout −25° C. and about 120° C.
 92. The method of claim 91, wherein theoxidation is performed at a temperature between about −25° C. and about0° C.
 93. The method of claim 60 or claim 67, wherein the carbon atom towhich R² and R³ are attached is a chiral center.
 94. The method of claim93, wherein the compound of Formulae (VI) or (VII) is not a racemate.95. A pharmaceutical composition comprising a compound of claim 1 or 16and a pharmaceutically acceptable vehicle